Fused heterocyclic compounds as ion channel modulators

ABSTRACT

The present disclosure relates to compounds that are sodium channel inhibitors and to their use in the treatment of various disease states, including cardiovascular diseases and diabetes. In particular embodiments, the structure of the compounds is given by Formula I: 
     
       
         
         
             
             
         
       
     
     wherein X, Y, Z, R 2 , R 3 , R 4 , p and q are as described herein, to methods for the preparation and use of the compounds and to pharmaceutical compositions containing the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit under 35 U.S.C. §119(e) to U.S.Provisional Application Ser. No. 61/919,605, filed on Dec. 20, 2013, theentirety of which is incorporated herein by reference.

FIELD

The present disclosure relates to novel compounds and to their use inthe treatment of various diseases, including cardiovascular diseases anddiabetes. The disclosure also relates to methods for preparation of thecompounds and to pharmaceutical compositions comprising such compounds.

BACKGROUND

The late sodium current (INaL) is a sustained component of the fast Na+current of cardiac myocytes and neurons. Many common neurological andcardiac conditions are associated with abnormal (INaL) enhancement,which contributes to the pathogenesis of both electrical and contactiledysfunction in mammals (particularly humans) See, for example,Pathophysiology and Pharmacology of the Cardiac “Late Sodium Current”,Pharmacology and Therapeutics 119 (2008) 326-339. Accordingly, compoundsthat selectively inhibit (INaL) in mammals, particularly humans, areuseful in treating such disease states.

It would be desirable to provide novel compounds that selectivelyinhibit (INaL) in mammals, particularly humans.

SUMMARY

Accordingly, embodiments the present disclosure provide novel compoundsthat function as late sodium channel blockers. In one embodiment, thedisclosure provides compounds of Formula I:

-   -   wherein    -   Y is -L-R¹ or a heterocyclyl or heteroaryl ring bonded through a        ring nitrogen atom, wherein each heterocyclyl or heteroaryl is        optionally substituted with 1 to 3 groups independently selected        from the group consisting of C₁-C₆ alkyl, C₃-C₆ cycloalkyl,        halo, aryl, heterocyclyl, heteroaryl, oxo, C₁-C₆ alkoxy, —OH,        —NH₂, —COR⁷, —CO₂R⁷, —NHSO₂R⁷, —NHCO₂R⁷, and —CN; and wherein        each C₁-C₆ alkyl, C₃-C₆ cycloalkyl, aryl, heterocyclyl,        heteroaryl, and C₁-C₆ alkoxy is optionally substituted with 1 to        3 C₁-C₆ alkoxy, halo, —CF₃, —CN, —OH, —NH₂ or —OCF₃;    -   X is CR⁸ or N;    -   Z is CR⁹ or N;    -   L is —O—, —NR⁵—, —NR⁵(CHR⁶)_(n)—, —O(CHR⁶)_(n)—O(CHR⁶)_(n)C(O)—,        —O(CHR⁶)—C(O)O—, —O(CHR⁶)_(n)NH—, —O(CHR⁶)—C(O)NH—,        —O(CHR⁶)—NHC(O)O— or —O(CHR⁶)_(m)NHS(O)₂—;    -   R¹ is hydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, aryl,        heterocyclyl or heteroaryl; wherein each cycloalkyl, aryl,        heterocyclyl or heteroaryl is optionally substituted with 1 to 3        groups independently selected from the group consisting of C₁-C₆        alkyl, C₃-C₆ cycloalkyl, halo, aryl, heterocyclyl, heteroaryl,        oxo, —OH, —NH₂, —COR⁷, —CO₂R⁷, —NHSO₂R⁷, —NHCO₂R⁷, and —CN; and        wherein each C₁-C₆ alkyl, C₃-C₆ cycloalkyl, aryl, heterocyclyl,        heteroaryl, and C₁-C₆ alkoxy is optionally substituted with 1 to        3 C₁-C₆ alkoxy, halo, —CF₃, —CN, —OH, —NH₂ or —OCF₃;    -   each R² is independently halo, C₁-C₆ alkyl, C₁-C₆ alkoxy or        —OCF₃;    -   R³ is hydrogen, halo, C₁-C₃ haloalkyl, C₁-C₃ haloalkoxy, C₃-C₆        cycloalkyl or phenyl, wherein the cycloalkyl or phenyl is        optionally substituted with one or two halo atoms, provided that        when R³ is hydrogen, then p is 1 or 2;    -   each R⁴ is independently C₁-C₆ alkyl, halo, C₁-C₆ alkoxy or        —OCF₃; or R³ and R⁴ taken together with the carbon atoms to        which they are attached form a C₄-C₈ ring optionally containing        from one to three double bonds and optionally containing from        one to three heteroatoms independently selected from the group        consisting of O, N, and S, which ring can be optionally        substituted with one to three halo, C₁-C₆ alkyl, C₁-C₃ haloalkyl        or C₁-C₃ haloalkoxy;    -   R⁵ is hydrogen, C₁-C₆ alkyl, C₁-C₃ haloalkyl or —COCH₃;    -   each R⁶ is independently hydrogen, C₁-C₆ alkyl, C₁-C₃ haloalkyl,        —CN, —OH or —NH₂;    -   R⁷ is hydrogen, C₁-C₆ alkyl, aryl or aralkyl;    -   R⁸ is independently hydrogen, C₁-C₆ alkyl, halo, C₁-C₆ alkoxy or        —OCF₃; or R³ and R⁸ taken together with the carbon atoms to        which they are attached form a C₄-C₈ ring optionally containing        from one to three double bonds and optionally containing from        one to three heteroatoms independently selected from the group        consisting of O, N, and S, which ring can be optionally        substituted with one to three halo, C₁-C₆ alkyl, C₁-C₃ haloalkyl        or C₁-C₃ haloalkoxy;    -   R⁹ is hydrogen, halo, C₁-C₆ alkyl, C₁-C₆ alkoxy or —OCF₃;    -   each m is independently 2, 3, 4 or 5;    -   each n is independently 1, 2, 3, 4 or 5; and    -   p and q are each independently 0, 1 or 2;    -   or a pharmaceutically acceptable salt, stereoisomer or mixture        of stereoisomer thereof.

In another embodiment, the disclosure provides compounds of Formula IA:

In yet another embodiment, the disclosure provides compounds of FormulaIB:

In still another embodiment, the disclosure provides compounds ofFormula IC:

In still another embodiment, the disclosure provides compounds ofFormula ID:

Some embodiments provide a method of using the compounds of Formula I,IA, IB, IC or ID, or additional Formula(s) described throughout, in thetreatment of a disease or condition in a mammal, particularly a human,that is amenable to treatment by a late sodium channel blocker. Suchdiseases include cardiovascular diseases such as atrial and ventriculararrhythmias, heart failure (including congestive heart failure,diastolic heart failure, systolic heart failure, acute heart failure),Prinzmetal's (variant) angina, stable and unstable angina, exerciseinduced angina, congestive heart disease, ischemia, recurrent ischemia,reperfusion injury, myocardial infarction, acute coronary syndrome,peripheral arterial disease and intermittent claudication. Such diseasesmay also include diabetes and conditions related to diabetes, e.g.diabetic peripheral neuropathy. Such diseases may also includeconditions affecting the neuromuscular system resulting in pain,seizures or paralysis. Such diseases may also include long QT syndrome(i.e., LQT1, LQT2, LQT3, LQT4 or LQT5), including, but not limited to,reducing a prolongation of the QT interval caused by a genetic mutationof SCN5A. Such diseases may also include hypertrophic cardiomyopathy.Therefore, it is contemplated that the compounds of the disclosure andtheir pharmaceutically acceptable salt, ester, stereoisomer, mixture ofstereoisomers and/or tautomer forms are potentially of use asmedicaments for the treatment of the aforementioned diseases.

In certain embodiments, the disclosure provides pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof the disclosure (e.g. a compound of Formula I or additional Formulasdescribed throughout), and at least one pharmaceutically acceptableexcipient.

The inventions of this disclosure are described throughout. In addition,specific embodiments of the invention are as disclosed herein.

DETAILED DESCRIPTION 1. Definitions and General Parameters

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having from 1 to 20 carbon atoms, or from 1to 15 carbon atoms, or from 1 to 10 carbon atoms, or from 1 to 8 carbonatoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms. Thisterm is exemplified by groups such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl,and the like.

The term “alkylene” refers to a diradical of a branched or unbranchedsaturated hydrocarbon chain, in some embodiments, having from 1 to 20carbon atoms (e.g. 1-10 carbon atoms or 1, 2, 3, 4, 5 or 6 carbonatoms). This term is exemplified by groups such as methylene (—CH₂—),ethylene (—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and—CH(CH₃)CH₂—), and the like.

The term “aralkyl” refers to an aryl group covalently linked to analkylene group, where aryl and alkylene are defined herein. “Optionallysubstituted aralkyl” refers to an optionally substituted aryl groupcovalently linked to an optionally substituted alkylene group. Sucharalkyl groups are exemplified by benzyl, phenylethyl,3-((4-methoxyphenyl)propyl, and the like.

The term “aralkyloxy” refers to the group —O-aralkyl. “Optionallysubstituted aralkyloxy” refers to an optionally substituted aralkylgroup covalently linked to an optionally substituted alkylene group.Such aralkyl groups are exemplified by benzyloxy, phenylethyloxy, andthe like.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group having from 2 to 20 carbon atoms (in someembodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) andhaving from 1 to 6 carbon-carbon double bonds, e.g. 1, 2 or 3carbon-carbon double bonds. In some embodiments, alkenyl groups includeethenyl (or vinyl, i.e. —CH═CH₂), 1-propylene (or allyl, i.e.—CH₂CH═CH₂), isopropylene (—C(CH₃)═CH₂), and the like.

The term “alkenylene” refers to a diradical of a branched or unbranchedunsaturated hydrocarbon group having from 2 to 20 carbon atoms (in someembodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) andhaving from 1 to 6 carbon-carbon double bonds, e.g. 1, 2 or 3carbon-carbon double bonds.

The term “alkynyl” refers to a monoradical of an unsaturatedhydrocarbon, in some embodiments, having from 2 to 20 carbon atoms (insome embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms)and having from 1 to 6 carbon-carbon triple bonds e.g. 1, 2 or 3carbon-carbon triple bonds. In some embodiments, alkynyl groups includeethynyl (—C≡CH), propargyl (or propynyl, i.e. —C≡CCH₃)), and the like.

The term “alkynylene” refers to a diradical of an unsaturatedhydrocarbon, in some embodiments, having from 2 to 20 carbon atoms (insome embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms)and having from 1 to 6 carbon-carbon triple bonds e.g. 1, 2 or 3carbon-carbon triple bonds.

The term “hydroxy” or “hydroxyl” refers to a group —OH.

The term “alkoxy” refers to the group R—O—, where R is alkyl or —Y¹—Z¹,in which Y¹ is alkylene and Z¹ is alkenyl or alkynyl, where alkyl,alkenyl and alkynyl are as defined herein. In some embodiments, alkoxygroups are alkyl-O— and includes, by way of example, methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy,n-hexyloxy, 1,2-dimethylbutoxy, and the like.

The term “C₁₋₃haloalkyl” refers to an alkyl group having from 1 to 3carbon atoms covalently bonded to from 1 to 7, or from 1 to 6, or from 1to 3, halogen(s), where alkyl and halogen are defined herein. In someembodiments, C₁₋₃haloalkyl includes, by way of example, trifluoromethyl,difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl,2-fluoroethyl, 3,3,3-trifluoropropyl, 3,3-difluoropropyl,3-fluoropropyl.

The term “C₁₋₃ hydroxyalkyl” refers to an alkyl group having a carbonatom covalently bonded to a hydroxy, where alkyl and hydroxy are definedherein. In some embodiments, C₁₋₃ hydroxyalkyl includes, by way ofexample, 2-hydroxyethyl.

The term “C₁₋₃ cyanoalkyl” refers to an alkyl group having a carbon atomcovalently bonded to a cyano, where alkyl and cyano are defined herein.In some embodiments, C₁₋₃ cyanoalkyl includes, by way of example,2-cyanoethyl.

The term “C₁₋₃ haloalkoxy” refers to an alkoxy group having from 1 to 3carbon atoms covalently bonded to from 1 to 7, or from 1 to 6, or from 1to 3, halogen(s), where alkyl and halogen are defined herein. In someembodiments, C₁₋₃ haloalkoxy includes, by way of example,trifluoromethoxy, difluoromethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy,2,2-difluoroethoxy, 2-fluoroethoxy, 3,3,3-trifluoropropoxy,3,3-difluoropropoxy, 3-fluoropropoxy.

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms, or from 3 to 10 carbon atoms, having a single cyclic ringor multiple condensed rings. Such cycloalkyl groups include, by way ofexample, single ring structures such as cyclopropyl, cyclobutyl,cyclopentyl, cyclooctyl and the like or multiple ring structures such asadamantanyl and bicyclo[2.2.1]heptanyl or cyclic alkyl groups to whichis fused an aryl group, for example indanyl, and the like, provided thatthe point of attachment is through the cyclic alkyl group.

The term “cycloalkenyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings andhaving at least one double bond and in some embodiments, from 1 to 2double bonds.

The term “cycloalkoxy” refers to the group cycloalkyl-O—.

The term “cycloalkenyloxy” refers to the group cycloalkenyl-O—.

The term “aryl” refers to an aromatic carbocyclic group of 6 to 20carbon atoms having a single ring (e.g., phenyl) or multiple rings(e.g., biphenyl) or multiple condensed (fused) rings (e.g., naphthyl,fluorenyl and anthryl). In some embodiments, aryls include phenyl,fluorenyl, naphthyl, anthryl, and the like.

The term “aryloxy” refers to the group aryl-O— wherein the aryl group isas defined above.

The term “heterocyclyl,” “heterocycle,” or “heterocyclic” refers to amonoradical saturated group having a single ring or multiple condensedrings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms,and from 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus,and/or oxygen within the ring. In some embodiments, the heterocyclyl,”“heterocycle,” or “heterocyclic” group is linked to the remainder of themolecule through one of the heteroatoms within the ring.

The term “heterocycloxy” refers to the group —O-heterocyclyl.

The term “heteroaryl” refers to a group comprising single or multiplerings comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selectedfrom oxygen, nitrogen and sulfur within at least one ring. Examples ofaromatic heteroaryls include pyrrole, thiophene, pyridine, quinoline,pteridine.

Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl)or multiple condensed rings (e.g., indolizinyl, benzothiazole orbenzothienyl). Examples of nitrogen heterocyclyls and heteroarylsinclude, but are not limited to, pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, and the like as well as N-alkoxy-nitrogencontaining heteroaryl compounds.

The term “heteroaryloxy” refers to the group heteroaryl-O—.

The term “amino” refers to the group —NH₂.

The term “substituted amino” refers to the group —NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl provided that both Rgroups are not hydrogen or a group —Y²—Z², in which Y² is optionallysubstituted alkylene and Z² is alkenyl, cycloalkenyl or alkynyl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1, 2 or 3 substituents chosen from alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “alkyl amine” refers to R—NH₂ in which R is alkyl.

The term “dialkyl amine” refers to R—NHR in which each R isindependently an alkyl.

The term “trialkyl amine” refers to NR₃ in which each R is independentlyan alkyl.

The term “cyano” refers to the group —CN.

The term “azido” refers to a group

The term “keto” or “oxo” refers to a group ═O.

The term “carboxy” refers to a group —C(O)—OH.

The term “ester” or “carboxyester” refers to the group —C(O)OR, where Ris alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, which may beoptionally further substituted by alkyl, alkoxy, halogen, CF₃, amino,substituted amino, cyano or —S(O)_(n)R^(a), in which R^(a) is alkyl,aryl or heteroaryl and n is 0, 1 or 2.

The term “acyl” denotes the group —C(O)R, in which R is hydrogen, alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “carboxyalkyl” refers to the groups —C(O)O-alkyl or—C(O)O-cycloalkyl, where alkyl and cycloalkyl are as defined herein, andmay be optionally further substituted by alkyl, alkenyl, alkynyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “aminocarbonyl” refers to the group —C(O)NRR where each R isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, orheterocyclyl, or where both R groups are joined to form a heterocyclicgroup (e.g., morpholino). Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents selected from the group consisting of alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “acyloxy” refers to the group —OC(O)—R, in which R is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “acylamino” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents selected from the group consisting of alkyl, alkenyl,alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “alkoxycarbonylamino” refers to the group —N(R^(d))C(O)OR inwhich R is alkyl and R^(d) is hydrogen or alkyl. Unless otherwiseconstrained by the definition, each alkyl may optionally be furthersubstituted by 1, 2 or 3 substituents selected from the group consistingof alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano,cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a), in whichR^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “aminocarbonylamino” refers to the group —NR^(c)C(O)NRR,wherein R^(c) is hydrogen or alkyl and each R is hydrogen, alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “sulfoxide” refers to a group —S(O)R, in which R is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl.

The term “hydroxyamino” refers to the group —NHOH.

The term “halogen” or “halo” refers to fluoro, bromo, chloro and iodo.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not.

A “substituted” group includes embodiments in which a monoradicalsubstituent is bound to a single atom of the substituted group (e.g.forming a branch), and also includes embodiments in which thesubstituent may be a diradical bridging group bound to two adjacentatoms of the substituted group, thereby forming a fused ring on thesubstituted group.

Where a given group (moiety) is described herein as being attached to asecond group and the site of attachment is not explicit, the given groupmay be attached at any available site of the given group to anyavailable site of the second group. For example, a “alkyl-substitutedphenyl”, where the attachment sites are not explicit, may have anyavailable site of the alkyl group attached to any available site of thephenyl group. In this regard, an “available site” is a site of the groupat which a hydrogen of the group may be replaced with a substituent.

A compound of a given formula (e.g. the compound of Formula I, whichalso includes Formula I, IA, IB, IC or ID) is intended to encompass thecompounds of the disclosure, and the pharmaceutically acceptable salts,pharmaceutically acceptable esters, isomers, tautomers, solvates,isotopes, hydrates, polymorphs, and prodrugs of such compounds.Additionally, the compounds of the disclosure may possess one or moreasymmetric centers, and can be produced as a racemic mixture or asindividual enantiomers or diastereoisomers. The number of stereoisomerspresent in any given compound of a given formula depends upon the numberof asymmetric centers present (there are 2^(n) stereoisomers possiblewhere n is the number of asymmetric centers). The individualstereoisomers may be obtained by resolving a racemic or non-racemicmixture of an intermediate at some appropriate stage of the synthesis orby resolution of the compound by conventional means. The individualstereoisomers (including individual enantiomers and diastereoisomers) aswell as racemic and non-racemic mixtures of stereoisomers areencompassed within the scope of the present disclosure, all of which areintended to be depicted by the structures of this specification unlessotherwise specifically indicated.

“Isomers” are different compounds that have the same molecular formula.Isomers include stereoisomers, enantiomers and diastereomers.

“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term “(±)” is used to designate a racemic mixturewhere appropriate.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

The absolute stereochemistry is specified according to the Cahn IngoldPrelog R S system. When the compound is a pure enantiomer thestereochemistry at each chiral carbon may be specified by either R or S.Resolved compounds whose absolute configuration is unknown aredesignated (+) or (−) depending on the direction (dextro- orlaevorotary) that they rotate the plane of polarized light at thewavelength of the sodium D line.

Some of the compounds exist as tautomeric isomers. Tautomeric isomersare in equilibrium with one another. For example, amide containingcompounds may exist in equilibrium with imidic acid tautomers.Regardless of which tautomer is shown, and regardless of the nature ofthe equilibrium among tautomers, the compounds are understood by one ofordinary skill in the art to comprise both amide and imidic acidtautomers. Thus, the amide containing compounds are understood toinclude their imidic acid tautomers. Likewise, the imidic acidcontaining compounds are understood to include their amide tautomers.

The term “therapeutically effective amount” refers to an amount that issufficient to effect treatment, as defined below, when administered to amammal, particularly a human, in need of such treatment. Thetherapeutically effective amount will vary depending upon the subjectand disease condition being treated, the weight and age of the subject,the severity of the disease condition, the manner of administration andthe like, which can readily be determined by one of ordinary skill inthe art.

The term “polymorph” refers to different crystal structures of acrystalline compound. The different polymorphs may result fromdifferences in crystal packing (packing polymorphism) or differences inpacking between different conformers of the same molecule(conformational polymorphism).

The term “prodrug” refers to compounds of Formula I, IA, IB, IC or IDthat include chemical groups which, in vivo, can be converted and/or canbe split off from the remainder of the molecule to provide for theactive drug, a pharmaceutically acceptable salt thereof or abiologically active metabolite thereof.

Any formula or structure given herein, including Formula I, IA, IB, ICor ID compounds, is also intended to represent unlabeled forms as wellas isotopically labeled forms of the compounds. Isotopically labeledcompounds have structures depicted by the formulas given herein exceptthat one or more atoms are replaced by an atom having a selected atomicmass or mass number. Examples of isotopes that can be incorporated intocompounds of the disclosure include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but notlimited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F,³¹P, ³²P, ³⁵S, ³⁶Cl and ¹²⁵I. Various isotopically labeled compounds ofthe present disclosure, for example those into which radioactiveisotopes such as ³H, ¹³C and ¹⁴C are incorporated. Such isotopicallylabelled compounds may be useful in metabolic studies, reaction kineticstudies, detection or imaging techniques, such as positron emissiontomography (PET) or single-photon emission computed tomography (SPECT)including drug or substrate tissue distribution assays or in radioactivetreatment of patients.

The disclosure also included compounds of Formula I, IA, IB, IC or ID inwhich from 1 to n hydrogens attached to a carbon atom is/are replaced bydeuterium, in which n is the number of hydrogens in the molecule. Suchcompounds exhibit increased resistance to metabolism and are thus usefulfor increasing the half life of any compound of Formula I whenadministered to a mammal, particularly a human. See, for example,Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”,Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds aresynthesized by means well known in the art, for example by employingstarting materials in which one or more hydrogens have been replaced bydeuterium.

Deuterium labelled or substituted therapeutic compounds of thedisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life, reduced dosage requirements and/oran improvement in therapeutic index. An ¹⁸F labeled compound may beuseful for PET or SPECT studies. Isotopically labeled compounds of thisdisclosure and prodrugs thereof can generally be prepared by carryingout the procedures disclosed in the schemes or in the examples andpreparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent. Itis understood that deuterium in this context is regarded as asubstituent in the compound of Formula I.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

The term “treatment” or “treating” means any administration of acompound(s) of the disclosure to a mammal (e.g. a human) having adisease alleviable by Late I_(Na) inhibition for the purpose of:

-   -   (i) preventing the disease, that is, causing the clinical        symptoms of the disease not to develop;    -   (ii) inhibiting the disease, that is, arresting the development        of clinical symptoms; and/or    -   (iii) relieving the disease, that is, causing the regression of        clinical symptoms.

In many cases, the compounds of this disclosure are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

The term “pharmaceutically acceptable salt” of a given compound refersto salts that retain the biological effectiveness and properties of thegiven compound, and which are not biologically or otherwise undesirable.Pharmaceutically acceptable base addition salts can be prepared frominorganic and organic bases. Salts derived from inorganic bases include,by way of example only, sodium, potassium, lithium, ammonium, calciumand magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary and tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl) amines, tri(substituted alkenyl) amines, mono,di or tri cycloalkyl amines, mono, di or tri arylamines or mixed amines,etc. Specific examples of suitable amines include, by way of exampleonly, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl)amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol,piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

Pharmaceutically acceptable acid addition salts may be prepared frominorganic and organic acids. Salts derived from inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid,salicylic acid, and the like.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents and the like. The use of suchmedia and agents for pharmaceutically active substances is well known inthe art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

“Coronary diseases” or “cardiovascular diseases” refer to diseases ofthe cardiovasculature arising from any one or more than one of, forexample, heart failure (including congestive heart failure, diastolicheart failure and systolic heart failure), acute heart failure,ischemia, recurrent ischemia, myocardial infarction, arrhythmias, angina(including exercise-induced angina, variant angina, stable angina,unstable angina), acute coronary syndrome, diabetes and intermittentclaudication.

“Intermittent claudication” means the pain associated with peripheralartery disease. “Peripheral artery disease” or PAD is a type ofocclusive peripheral vascular disease (PVD). PAD affects the arteriesoutside the heart and brain. The most common symptom of PAD is a painfulcramping in the hips, thighs or calves when walking, climbing stairs orexercising. The pain is called intermittent claudication. When listingthe symptom intermittent claudication, it is intended to include bothPAD and PVD.

Arrhythmia refers to any abnormal heart rate. Bradycardia refers toabnormally slow heart rate whereas tachycardia refers to an abnormallyrapid heart rate. As used herein, the treatment of arrhythmia isintended to include the treatment of supra ventricular tachycardias suchas atrial fibrillation, atrial flutter, AV nodal reentrant tachycardia,atrial tachycardia and the ventricular tachycardias (VTs), includingidiopathic ventricular tachycardia, ventricular fibrillation,pre-excitation syndrome and Torsade de Pointes (TdP).

“Long QT Syndrome” or “LQTS” is caused by dysfunction of proteinstructures in the heart cells called ion channels or protein structuresmodulating the activity of ion channels. These channels control the flowof ions like potassium, sodium and calcium molecules. The flow of theseions in and out of the cells produces the electrical activity of theheart. Abnormalities of these channels can be acquired or inherited. Theacquired form is usually caused by prescription medications, however,the inherited form occurs when a mutation develops in one of severalgenes that produce or “encode” one of the ion channels that controlelectrical repolarization. The mutant gene produces abnormal channels tobe formed, and as these abnormal channels are dysfunctional and theelectrical repolarization of the heart takes longer. This is manifestedon the electrocardiogram (ECG, EKG) by a prolonged QT interval.

“QT prolongation”, or a prolonged QT interval, makes the heartvulnerable to polymorphic ventricular tachycardias, one kind of which isa fast, abnormal heart rhythm known as Torsade de Pointes. The correctedQT interval (or “QTc”) represents the QT interval normalized for a heartrate of 60 beats/min. There are several methods for calculating the QTc,such as Bazett's formula (QT_(B)=QT/√RR), Fridericia's formula(QT_(B)=QT/³√RR), or a regression-based approach (QT_(LC)=QT+0.154(1−RR), where RR is the interval from the onset of one QRS complex tothe onset of the next QRS complex.

Congenital LQTS is caused by mutations in at least one of fifteen geneswith mutations in three genes accounting for approximately 70% ofgenotype positive cases (LQT1-LQT3):

Ion Channel Disease Gene Chromosome or Protein LQT1 KCNQ1 11p15.5 I_(Ks)subunit* (KVLQT1) LQT2 HERG 7q35-46 I_(Kr) LQT3 SCN5A 3q21-24 I_(Na)LQT4 ANKB 4q25-27 Ankyrin B LQT5 KCNE1 21q22.1 I_(Ks) subunit (MinK)*Homozygous carriers of novel mutations of KVLQT1 have Jervell,Lange-Nielsen syndrome. KVLQT1 and MinK coassemble to form the IKschannel.

The LQT diseases and ion channels listed in the table above are the samefor acquired LQTS as they are for inherited LQTS. The inherited form ofLQTS occurs when a mutation develops in one of several genes thatproduce or “encode” one of the ion channels or ion channel modulatorsthat control electrical repolarization. There are at least fifteendifferent forms of inherited LQTS, characterized as LQT1-LQT15. Theywere originally characterized by the differing shape of the ECG trace,and have subsequently been associated with specific gene mutations. TheLQT1 form is the most frequent, accounting for approximately 30-35% ofthe genotyped patients. LQT2 is next at about 25-30%, and LQT3, fromSCN5A mutations accounts for about 5-10%. Patients with two mutationsseem to account for less than 1% of all patients, but this may change asmore patients are studied with the newer genetic techniques.

“Hypertrophic cardiomyopathy” is a disease in which the heart muscle(myocardium) becomes abnormally thick or hypertrophied. This thickenedheart muscle can make it harder for the heart to pump blood.Hypertrophic cardiomyopathy may also affect the heart's electricalsystem. HCM is the most common genetic cardiac disease, affectingapproximately 1 in 500 people. It is caused by autosomal-dominantmutations in genes encoding critical components of the cardiacsarcomere. HCM is recognized clinically as unexplained left ventricular(LV) hypertrophy (typically ≧15 mm thickness of the ventricular wall) inthe absence of other cardiac or systemic conditions capable of producingthe magnitude of hypertrophy observed. Typical symptoms includeshortness of breath, angina, palpitations, fatigue and syncope. In asmall percentage of patients, sudden cardiac death may be the firstpresentation. HCM is a leading cause of sudden cardiac death in youngadults.

2. Nomenclature

Names of compounds of the present disclosure are provided using ACD/Namesoftware for naming chemical compounds (Advanced Chemistry Development,Inc., Toronto, Canada). Other compounds or radicals may be named withcommon names or systematic or non-systematic names. The naming andnumbering of the compounds of the disclosure is illustrated with arepresentative compound of Formula I:

which is named3-(pyrimidin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole.

3. Compounds

Accordingly, typical embodiments the present disclosure provide novelcompounds that function as late sodium channel blockers. In oneembodiment, the disclosure provides compounds of Formula I:

-   -   wherein    -   Y is -L-R¹ or a heterocyclyl or heteroaryl ring bonded through a        ring nitrogen atom, wherein each heterocyclyl or heteroaryl is        optionally substituted with 1 to 3 groups independently selected        from the group consisting of C₁-C₆ alkyl, C₃-C₆ cycloalkyl,        halo, aryl, heterocyclyl, heteroaryl, oxo, C₁-C₆ alkoxy, —OH,        —NH₂, —COR⁷, —CO₂R⁷, —NHSO₂R⁷, —NHCO₂R⁷, and —CN; and wherein        each C₁-C₆ alkyl, C₃-C₆ cycloalkyl, aryl, heterocyclyl,        heteroaryl, and C₁-C₆ alkoxy is optionally substituted with 1 to        3 C₁-C₆ alkoxy, halo, —CF₃, —CN, —OH, —NH₂ or —OCF₃;    -   X is CR⁸ or N;    -   Z is CR⁹ or N;    -   L is —O—, —NR⁵—, —NR⁵(CHR⁶)_(n)—, —O(CHR⁶)—, —O(CHR⁶)—C(O)—,        —O(CHR⁶)—C(O)O—, —O(CHR⁶)_(n)NH—, —O(CHR⁶)—C(O)NH—,        —O(CHR⁶)—NHC(O)O— or —O(CHR⁶)_(m)NHS(O)₂—;    -   R¹ is hydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, aryl,        heterocyclyl or heteroaryl; wherein each cycloalkyl, aryl,        heterocyclyl or heteroaryl is optionally substituted with 1 to 3        groups independently selected from the group consisting of C₁-C₆        alkyl, C₃-C₆ cycloalkyl, halo, aryl, heterocyclyl, heteroaryl,        oxo, —OH, —NH₂, —COR⁷, —CO₂R⁷, —NHSO₂R⁷, —NHCO₂R⁷, and —CN; and        wherein each C₁-C₆ alkyl, C₃-C₆ cycloalkyl, aryl, heterocyclyl,        heteroaryl, and C₁-C₆ alkoxy is optionally substituted with 1 to        3 C₁-C₆ alkoxy, halo, —CF₃, —CN, —OH, —NH₂ or —OCF₃;    -   each R² is independently halo, C₁-C₆ alkyl, C₁-C₆ alkoxy or        —OCF₃;    -   R³ is hydrogen, halo, C₁-C₃ haloalkyl, C₁-C₃ haloalkoxy, C₃-C₆        cycloalkyl or phenyl, wherein the cycloalkyl or phenyl is        optionally substituted with one or two halo atoms, provided that        when R³ is hydrogen, then p is 1 or 2;    -   each R⁴ is independently C₁-C₆ alkyl, halo, C₁-C₆ alkoxy or        —OCF₃; or R³ and R⁴ taken together with the carbon atoms to        which they are attached form a C₄-C₈ ring optionally containing        from one to three double bonds and optionally containing from        one to three heteroatoms independently selected from the group        consisting of O, N, and S, which ring can be optionally        substituted with one to three halo, C₁-C₆ alkyl, C₁-C₃ haloalkyl        or C₁-C₃ haloalkoxy;    -   R⁵ is hydrogen, C₁-C₆ alkyl, C₁-C₃ haloalkyl or —COCH₃;    -   each R⁶ is independently hydrogen, C₁-C₆ alkyl, C₁-C₃ haloalkyl,        —CN, —OH or —NH₂;    -   R⁷ is hydrogen, C₁-C₆ alkyl, aryl or aralkyl;    -   R⁸ is independently hydrogen, C₁-C₆ alkyl, halo, C₁-C₆ alkoxy or        —OCF₃; or R³ and R⁸ taken together with the carbon atoms to        which they are attached form a C₄-C₈ ring optionally containing        from one to three double bonds and optionally containing from        one to three heteroatoms independently selected from the group        consisting of O, N, and S, which ring can be optionally        substituted with one to three halo, C₁-C₆ alkyl, C₁-C₃ haloalkyl        or C₁-C₃ haloalkoxy;    -   R⁹ is hydrogen, halo, C₁-C₆ alkyl, C₁-C₆ alkoxy or —OCF₃;    -   each m is independently 2, 3, 4 or 5;    -   each n is independently 1, 2, 3, 4 or 5; and    -   p and q are each independently 0, 1 or 2;    -   or a pharmaceutically acceptable salt, stereoisomer or mixture        of stereoisomer thereof.

In another embodiment, the disclosure provides compounds of Formula IA:

In yet another embodiment, the disclosure provides compounds of FormulaIB:

In still another embodiment, the disclosure provides compounds ofFormula IC:

In still another embodiment, the disclosure provides compounds ofFormula ID:

In some embodiments, Y is a heterocyclyl or heteroaryl ring bondedthrough a ring nitrogen atom, wherein each heterocyclyl or heteroaryl isoptionally substituted with 1 to 3 groups independently selected fromthe group consisting of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, aryl,heterocyclyl, heteroaryl, oxo, C₁-C₆ alkoxy, —OH, —NH₂, —COR⁷, —CO₂R⁷,—NHSO₂R⁷, —NHCO₂R⁷, and —CN; and wherein each C₁-C₆ alkyl, C₃-C₆cycloalkyl, aryl, heterocyclyl, heteroaryl, and C₁-C₆ alkoxy isoptionally substituted with 1 to 3 C₁-C₆ alkoxy, halo, —CF₃, —CN, —OH,—NH₂ or —OCF₃.

In some embodiments, Y is a heterocyclyl or heteroaryl ring bondedthrough a ring nitrogen atom, wherein each heterocyclyl or heteroaryl isoptionally substituted with 1 to 3 groups independently selected fromthe group consisting of C₁-C₆ alkyl, aryl, and oxo, wherein the C₁-C₆alkyl is optionally substituted with 1 to 3 halo or —OH.

In some embodiments, Y is -L-R¹.

In some embodiments, L is —O(CHR⁶)_(n)—.

In some embodiments, each R⁶ is independently hydrogen or C₁-C₆ alkyl.

In some embodiments, R¹ is hydrogen.

In some embodiments, R¹ is C₁-C₆ alkyl.

In some embodiments, R¹ is C₃-C₈ cycloalkyl, aryl, heterocyclyl orheteroaryl; wherein each cycloalkyl, aryl, heterocyclyl or heteroaryl isoptionally substituted with 1 to 3 groups independently selected fromthe group consisting of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, aryl,heterocyclyl, heteroaryl, oxo, —OH, —NH₂, —COR⁷, —CO₂R⁷, —NHSO₂R⁷,—NHCO₂R⁷, and —CN; and wherein each C₁-C₆ alkyl, C₃-C₆ cycloalkyl, aryl,heterocyclyl, heteroaryl, and C₁-C₆ alkoxy is optionally substitutedwith 1 to 3 C₁-C₆ alkoxy, halo, —CF₃, —CN, —OH, —NH₂ or —OCF₃.

In some embodiments, R¹ is

In some embodiments, R¹ is hydrogen or C₁-C₆ alkyl. In some embodiments,R¹ is C₁-C₆ alkyl. In certain embodiments, when R¹ is hydrogen or C₁-C₆alkyl, then L is not —O— or —NR⁵—.

In some embodiments, R² is fluoro, methyl or methoxy.

In some embodiments, R³ is halogen, C₁-C₃ haloalkyl, C₁-C₃ haloalkoxy,C₃-C₆ cycloalkyl or phenyl, wherein the cycloalkyl or phenyl isoptionally substituted with one or two halogen atoms.

In some embodiments, R³ is hydrogen, fluoro, —CF₃, —OCF₃, —O—CH₂—CF₃ orcyclopropyl.

In some embodiments, R⁴ is fluoro, chloro, methyl, methoxy or —OCF₃.

In some embodiments, X is N.

In some embodiments, X is CR⁸.

In some embodiments, R⁸ is hydrogen.

In some embodiments, Z is N.

In some embodiments, Z is CR⁹.

In some embodiments, R⁹ is hydrogen.

In some embodiments, q is 0 or 1. In some embodiments, q is 0. In someembodiments, q is 1.

In some embodiments, p is 0 or 1. In some embodiments, p is 0. In someembodiments, p is 1.

In some embodiments, the compound is selected from the group consistingof

-   3-(pyrimidin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   5-(2-fluoro-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   5-(2-methyl-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   5-(2-methoxy-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   3-((4-methylpyrimidin-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   5-(2-fluoro-4-(trifluoromethyl)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   5-(3-methyl-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   5-(4-chloro-3-fluorophenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   3-(pyrimidin-2-ylmethoxy)-5-(4-(trifluoromethyl)phenyl)benzo[d]isoxazole;-   3-(pyrimidin-2-ylmethoxy)-5-(3-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   6-methoxy-3-(pyrimidin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   5-(2-fluoro-4-(trifluoromethyl)phenyl)-6-methoxy-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   5-(4-chloro-3-fluorophenyl)-6-methoxy-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   6-methoxy-5-(3-methyl-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   5-(3-chloro-4-fluorophenyl)-6-methoxy-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   7-methyl-3-(pyrimidin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   7-fluoro-3-(pyrimidin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   7-methyl-5-(3-methyl-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   7-methyl-3-(pyrimidin-2-ylmethoxy)-5-(3-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   5-(6-cyclopropylpyridin-3-yl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   3-(pyrimidin-2-ylmethoxy)-5-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)benzo[d]isoxazole;-   7-methoxy-3-(pyrimidin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   7-methoxy-5-(3-methyl-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   5-(2-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   7-methoxy-5-(2-methyl-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   6-ethyl-3-(pyrimidin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   6-methyl-5-(3-methyl-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   5-(2-fluoro-4-(trifluoromethyl)phenyl)-6-methyl-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   6-methyl-5-(2-methyl-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   6-fluoro-3-(pyrimidin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   6-fluoro-5-(3-methyl-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   6-fluoro-5-(2-fluoro-4-(trifluoromethyl)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   6-fluoro-5-(2-methyl-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-6-fluoro-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole;-   3-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methoxy)-5-(2-methyl-4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methoxy)-5-(4-(trifluoromethyl)phenyl)benzo[d]isoxazole;-   3-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methoxy)-5-(2-fluoro-4-(trifluoromethyl)phenyl)benzo[d]isoxazole;-   3-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methoxy)-5-(2-methoxy-4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methoxy)-5-(3-methyl-4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methoxy)-5-(2-fluoro-4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-(oxetan-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((1-methyl-1H-imidazol-4-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((1-methyl-1H-imidazol-4-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((1H-pyrazol-4-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   4-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole-3-yl)oxy)methyl)pyrrolidin-2-one;-   3-((1-ethyl-1H-imidazol-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((1-isopropyl-1H-imidazol-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((1-ethyl-1H-imidazol-5-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((1-methyl-1H-imidazol-5-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((2,5-dimethyloxazol-4-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-(oxazol-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   2-(1-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)cyclopropyl)acetonitrile;-   3-(2-(1H-imidazol-1-yl)ethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   1-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)pyrrolidin-2-one;-   3-(2-(2-methyl-1H-imidazol-1-yl)ethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   1-(2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)ethyl)pyrrolidin-2-one;-   3-(2-methoxyethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   (R)-5-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)pyrrolidin-2-one;-   (S)-5-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)pyrrolidin-2-one;-   3-(2-(4H-1,2,4-triazol-4-yl)    ethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((1-phenyl-1H-imidazol-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((1-(pyridin-2-yl)-1H-pyrazol-4-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-(2-(1H-imidazol-2-yl)ethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((4-methoxypyrimidin-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-(2-(1H-pyrazol-1-yl)propoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((4-morpholinopyrimidin-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   (S)-3-((1-methylpyrrolidin-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   (R)-3-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)pyrrolidin-2-one;-   3-((5-methylpyrazin-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-(pyridazin-3-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-(2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)ethyl)oxazolidin-2-one;-   3-(2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)ethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-(2-(1H-1,2,4-triazol-1-yl)propoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-(2-morpholinoethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-(2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)propoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   1-(2-((7-fluoro-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)ethyl)pyrrolidin-2-one;-   3-((4-methoxypyridin-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-(isoquinolin-3-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((1H-1,2,3-triazol-4-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-7-fluoro-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   4-(2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)ethyl)thiomorpholine    1,1-dioxide;-   5-(4-(trifluoromethoxy)phenyl)-3-((4-(trifluoromethyl)pyrimidin-2-yl)methoxy)benzo[d]isoxazole;-   7-methyl-3-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   1-(2-((7-methyl-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)ethyl)pyrrolidin-2-one;-   3-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-7-methyl-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((4-methoxypyrimidin-2-yl)methoxy)-7-methyl-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   7-methyl-3-(oxazol-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((3-methyloxetan-3-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((3-methylpyridin-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((3-fluoropyridin-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((6-methylpyridin-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   (3-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)oxetan-3-yl)methanol;-   3-(1-(pyridin-2-yl)ethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-(((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-(((5-isopropyl-1,3,4-oxadiazol-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-(((5-methyl-1,3,4-thiadiazol-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((3-methylisoxazol-5-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)acetonitrile;-   3-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methoxy)-7-fluoro-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methoxy)-7-methyl-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   7-methyl-3-((6-methylpyridin-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   tert-butyl    (S)-2-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)pyrrolidine-1-carboxylate;-   (S)-3-(pyrrolidin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   (S)-1-(2-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethan-1-one;-   1-(3-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)azetidin-1-yl)ethan-1-one;-   tert-butyl    (S)-3-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)morpholine-4-carboxylate;-   tert-butyl    (R)-3-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)morpholine-4-carboxylate;-   (S)-3-(morpholin-3-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   (R)-3-(morpholin-3-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   (S)-1-(3-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)morpholino)ethan-1-one;-   (R)-1-(3-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)morpholino)ethan-1-one;-   (R)-1-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)propan-2-amine;-   (S)-3-methyl-1-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)butan-2-amine;-   (R)-1-(1-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)propan-2-yl)pyrrolidin-2-one;-   (S)-1-(3-methyl-1-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)butan-2-yl)pyrrolidin-2-one;-   1-(pyrrolidin-1-yl)-2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)ethan-1-one;-   N-isopropyl-2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)acetamide;-   N-(2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)ethyl)pyrimidin-2-amine;-   3-(pyrimidin-2-yloxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-(pyridin-2-yloxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   N-(pyrimidin-2-ylmethyl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-amine;-   3-((4-methylpiperazin-1-yl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   N-(cyclopropylmethyl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-amine;-   N-((6-methylpyridin-2-yl)methyl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-amine;-   3-morpholino-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   N-isopropyl-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-amine;-   3-(1H-imidazol-1-yl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   N,N-dimethyl-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-amine;-   (R)-5-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)amino)methyl)pyrrolidin-2-one;-   1-(2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)amino)ethyl)pyrrolidin-2-one;-   3-(1H-1,2,4-triazol-1-yl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-amine;-   3-(2-methyl-1H-imidazol-1-yl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((4-methyl-1H-imidazol-1-yl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((4-chloro-1H-imidazol-1-yl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((3-methyl-1H-1,2,4-triazol-1-yl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((4-phenyl-1H-imidazol-1-yl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-(4-(tert-butyl)-1H-imidazol-1-yl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-(2-isopropyl-1H-imidazol-1-yl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   5-(4-(trifluoromethoxy)phenyl)-3-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzo[d]isoxazole;-   (1-(5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)-1H-imidazol-4-yl)methanol;-   5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-amine;-   3-(pyrimidin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)isoxazolo[5,4-c]pyridine;-   N-((4-methoxypyrimidin-2-yl)methyl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-amine;-   N,N-diethyl-2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)acetamide;-   3-(pyrazin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((3-methylpyrazin-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-(1-(5-methyl-1,3,4-oxadiazol-2-yl)ethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   3-((5-cyclopropyl-1,3,4-thiadiazol-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   7-fluoro-3-(((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole;-   N-(oxazol-2-ylmethyl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-amine;    and-   tert-butyl    2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)acetate;-   or a pharmaceutically acceptable salt, stereoisomer or mixture of    stereoisomer thereof.

4. Further Embodiments

In some embodiments, the compounds provided by the present disclosureare effective in the treatment of conditions or diseases known torespond to administration of late sodium channel blockers, including butnot limited to cardiovascular diseases such as atrial and ventriculararrhythmias, including atrial fibrillation, Prinzmetal's (variant)angina, stable angina, unstable angina, ischemia and reperfusion injuryin cardiac, kidney, liver and the brain, exercise induced angina,pulmonary hypertension, congestive heart disease including diastolic andsystolic heart failure, and myocardial infarction. In some embodiments,compounds provided by the present disclosure which function as latesodium channel blockers may be used in the treatment of diseasesaffecting the neuromuscular system resulting in pain, itching, seizures,or paralysis, or in the treatment of diabetes or reduced insulinsensitivity, and disease states related to diabetes, such as diabeticperipheral neuropathy.

Certain compounds of the disclosure may also possess a sufficientactivity in modulating neuronal sodium channels, i.e., Na_(v) 1.1., 1.2,1.3, 1.7, and/or 1.8, and may have appropriate pharmacokineticproperties such that they may be active with regard to the centraland/or peripheral nervous system. Consequently, some compounds of thedisclosure may also be of use in the treatment of epilepsy or pain oritching or headache of a neuropathic origin.

In one embodiment, this disclosure provides a method of treating adisease state in a mammal, particularly a human, that is alleviable bytreatment with an agent capable of reducing late sodium current,comprising administering to a mammal, particularly a human, in needthereof a therapeutically effective dose of a compound of Formula I, IA,IB, IC or ID or other formulas or compounds disclosed herein. In anotherembodiment, the disease state is a cardiovascular disease selected fromone or more of atrial and ventricular arrhythmias, heart failure(including congestive heart failure, diastolic heart failure, systolicheart failure, acute heart failure), Prinzmetal's (variant) angina,stable and unstable angina, exercise induced angina, congestive heartdisease, ischemia, recurrent ischemia, reperfusion injury, myocardialinfarction, acute coronary syndrome, peripheral arterial disease,pulmonary hypertension, and intermittent claudication.

In another embodiment, the disease state is diabetes or diabeticperipheral neuropathy. In a further embodiment, the disease stateresults in one or more of neuropathic pain, epilepsy, headache,seizures, or paralysis.

In one embodiment, this disclosure provides a method of treatingdiabetes in a mammal, particularly a human, comprising administering toa mammal in need thereof a therapeutically effective dose of a compoundof Formula I, IA, IB, IC or ID or other formulas or compounds disclosedherein. Diabetes mellitus is a disease characterized by hyperglycemia;altered metabolism of lipids, carbohydrates and proteins; and anincreased risk of complications from vascular disease. Diabetes is anincreasing public health problem, as it is associated with bothincreasing age and obesity.

There are two major types of diabetes mellitus: 1) Type I, also known asinsulin dependent diabetes (IDDM) and 2) Type II, also known as insulinindependent or non-insulin dependent diabetes (NIDDM). Both types ofdiabetes mellitus are due to insufficient amounts of circulating insulinand/or a decrease in the response of peripheral tissue to insulin.

Type I diabetes results from the body's failure to produce insulin, thehormone that “unlocks” the cells of the body, allowing glucose to enterand fuel them. The complications of Type I diabetes include heartdisease and stroke; retinopathy (eye disease); kidney disease(nephropathy); neuropathy (nerve damage); as well as maintenance of goodskin, foot and oral health.

Type II diabetes results from the body's inability to either produceenough insulin or the cells inability to use the insulin that isnaturally produced by the body. The condition where the body is not ableto optimally use insulin is called insulin resistance. Type II diabetesis often accompanied by high blood pressure and this may contribute toheart disease. In patients with type II diabetes mellitus, stress,infection, and medications (such as corticosteroids) can also lead toseverely elevated blood sugar levels. Accompanied by dehydration, severeblood sugar elevation in patients with type II diabetes can lead to anincrease in blood osmolality (hyperosmolar state). This condition canlead to coma.

It has been suggested that ranolazine (RANEXA®, a selective inhibitor ofINaL) may be an antidiabetic agent that causes β-cell preservation andenhances insulin secretion in a glucose-dependent manner in diabeticmice (see, Y. Ning et al. J Pharmacol Exp Ther. 2011, 337(1), 50-8).Therefore it is contemplated that the compounds of Formula I, IA, IB, ICor ID or other formulas or compounds disclosed herein can be used asantidiabetic agents for the treatment of diabetes.

5. Pharmaceutical Compositions and Administration

Compounds provided in accordance with the present disclosure are usuallyadministered in the form of pharmaceutical compositions. This disclosuretherefore provides pharmaceutical compositions that contain, as theactive ingredient, one or more of the compounds described, or apharmaceutically acceptable salt or ester thereof, and one or morepharmaceutically acceptable excipients, carriers, including inert soliddiluents and fillers, diluents, including sterile aqueous solution andvarious organic solvents, permeation enhancers, solubilizers andadjuvants. The pharmaceutical compositions may be administered alone orin combination with other therapeutic agents. Such compositions areprepared in a manner well known in the pharmaceutical art (see, e.g.,Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia,Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rdEd. (G. S. Banker & C. T. Rhodes, Eds.)

The pharmaceutical compositions may be administered in either single ormultiple doses by any of the accepted modes of administration of agentshaving similar utilities, for example as described in those patents andpatent applications incorporated by reference, including rectal, buccal,intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, as an inhalant, or via an impregnatedor coated device such as a stent, for example, or an artery-insertedcylindrical polymer.

One mode for administration is parenteral, particularly by injection.The forms in which the novel compositions of the present disclosure maybe incorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles. Aqueous solutions insaline are also conventionally used for injection, but less preferred inthe context of the present disclosure. Ethanol, glycerol, propyleneglycol, liquid polyethylene glycol, and the like (and suitable mixturesthereof), cyclodextrin derivatives, and vegetable oils may also beemployed. The proper fluidity can be maintained, for example, by the useof a coating, such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.The prevention of the action of microorganisms can be brought about byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating a compoundaccording to the present disclosure in the required amount in theappropriate solvent with various other ingredients as enumerated above,as required, followed by filtered sterilization. Generally, dispersionsare prepared by incorporating the various sterilized active ingredientsinto a sterile vehicle which contains the basic dispersion medium andthe required other ingredients from those enumerated above. In the caseof sterile powders for the preparation of sterile injectable solutions,the preferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof. Preferably, for parenteral administration, sterileinjectable solutions are prepared containing a therapeutically effectiveamount, e.g., 0.1 to 700 mg, of a compound described herein. It will beunderstood, however, that the amount of the compound actuallyadministered usually will be determined by a physician, in the light ofthe relevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered and itsrelative activity, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

Oral administration is another route for administration of compounds inaccordance with the disclosure. Administration may be via capsule orenteric coated tablets, or the like. In making the pharmaceuticalcompositions that include at least one compound described herein, theactive ingredient is usually diluted by an excipient and/or enclosedwithin such a carrier that can be in the form of a capsule, sachet,paper or other container. When the excipient serves as a diluent, it canbe in the form of a solid, semi-solid, or liquid material (as above),which acts as a vehicle, carrier or medium for the active ingredient.Thus, the compositions can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosols (as a solid or in a liquid medium), ointmentscontaining, for example, up to 10% by weight of the active compound,soft and hard gelatin capsules, sterile injectable solutions, andsterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions of the disclosure can be formulated so as to providequick, sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.Controlled release drug delivery systems for oral administration includeosmotic pump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations. Examples of controlledrelease systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;4,902,514; and 5,616,345. Another formulation for use in the methods ofthe present disclosure employs transdermal delivery devices (“patches”).Such transdermal patches may be used to provide continuous ordiscontinuous infusion of the compounds of the present disclosure incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is well known in the art. See,e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patchesmay be constructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

The compositions are preferably formulated in a unit dosage form. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient (e.g., a tablet, capsule, ampoule). Thecompounds are generally administered in a pharmaceutically effectiveamount. Preferably, for oral administration, each dosage unit containsfrom 1 mg to 2 g, or alternatively, or 100 mg to 500 mg, of a compounddescribed herein, and for parenteral administration, preferably from 0.1mg to 700 mg, or alternatively, 0.1 mg to 100 mg, of a compound acompound described herein. It will be understood, however, that theamount of the compound actually administered usually will be determinedby a physician, in the light of the relevant circumstances, includingthe condition to be treated, the chosen route of administration, theactual compound administered and its relative activity, the age, weight,and response of the individual patient, the severity of the patient'ssymptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present disclosure. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules.

The tablets or pills of the present disclosure may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can comprise an inner dosage and anouter dosage component, the latter being in the form of an envelope overthe former. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably, the compositions are administered by the oral ornasal respiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemasktent, or intermittent positive pressure breathing machine. Solution,suspension, or powder compositions may be administered, preferablyorally or nasally, from devices that deliver the formulation in anappropriate manner.

Combination Therapy

Patients being treated by administration of the late sodium channelblockers of the disclosure often exhibit diseases or conditions thatbenefit from treatment with other therapeutic agents. These diseases orconditions can be of cardiovascular nature or can be related topulmonary disorders, metabolic disorders, gastrointestinal disorders andthe like. Additionally, some coronary patients being treated byadministration of the late sodium channel blockers of the disclosureexhibit conditions that can benefit from treatment with therapeuticagents that are antibiotics, analgesics, and/or antidepressants andanti-anxiety agents.

Cardiovascular Agent Combination Therapy

Cardiovascular related diseases or conditions that can benefit from acombination treatment of the late sodium channel blockers of thedisclosure with other therapeutic agents include, without limitation,angina including stable angina, unstable angina (UA), exercised-inducedangina, variant angina, arrhythmias, intermittent claudication,myocardial infarction including non-STE myocardial infarction (NSTEMI),pulmonary hypertension including pulmonary arterial hypertension, heartfailure including congestive (or chronic) heart failure and diastolicheart failure and heart failure with preserved ejection fraction(diastolic dysfunction), acute heart failure, or recurrent ischemia.

Therapeutic agents suitable for treating cardiovascular related diseasesor conditions include anti-anginals, heart failure agents,antithrombotic agents, antiarrhythmic agents, antihypertensive agents,and lipid lowering agents.

The co-administration of the late sodium channel blockers of thedisclosure with therapeutic agents suitable for treating cardiovascularrelated conditions allows enhancement in the standard of care therapythe patient is currently receiving. In some embodiments, the late sodiumchannel blockers of the disclosure are co-administered with ranolazine(RANEXA®).

Anti-Anginals

Anti-anginals include beta-blockers, calcium channel blockers, andnitrates. Beta blockers reduce the heart's need for oxygen by reducingits workload resulting in a decreased heart rate and less vigorous heartcontraction. Examples of beta-blockers include acebutolol (Sectral®),atenolol (Tenormin®), betaxolol (Kerlone®),bisoprolol/hydrochlorothiazide (Ziac®), bisoprolol (Zebeta®), carteolol(Cartrol®), esmolol (Brevibloc®), labetalol (Normodyne®, Trandate®),metoprolol (Lopressor®, Toprol® XL), nadolol (Corgard®), propranolol(Inderal®), sotalol (Betapace®), and timolol (Blocadren®).

Nitrates dilate the arteries and veins thereby increasing coronary bloodflow and decreasing blood pressure. Examples of nitrates includenitroglycerin, nitrate patches, isosorbide dinitrate, andisosorbide-5-mononitrate.

Calcium channel blockers prevent the normal flow of calcium into thecells of the heart and blood vessels causing the blood vessels to relaxthereby increasing the supply of blood and oxygen to the heart. Examplesof calcium channel blockers include amlodipine (Norvasc®, Lotrel®),bepridil (Vascor®), diltiazem (Cardizem®, Tiazac®), felodipine(Plendil®), nifedipine (Adalat®, Procardia®), nimodipine (Nimotop®),nisoldipine (Sular®), verapamil (Calan®, Isoptin®, Verelan®), andnicardipine.

Heart Failure Agents

Agents used to treat heart failure include diuretics, ACE inhibitors,vasodilators, and cardiac glycosides. Diuretics eliminate excess fluidsin the tissues and circulation thereby relieving many of the symptoms ofheart failure. Examples of diuretics include hydrochlorothiazide,metolazone (Zaroxolyn®), furosemide (Lasix®), bumetanide (Bumex®),spironolactone (Aldactone®), and eplerenone (Inspra®).

Angiotensin converting enzyme (ACE) inhibitors reduce the workload onthe heart by expanding the blood vessels and decreasing resistance toblood flow. Examples of ACE inhibitors include benazepril (Lotensin®),captopril (Capoten®), enalapril (Vasotec®), fosinopril (Monopril®),lisinopril (Prinivil®, Zestril®), moexipril (Univasc®), perindopril(Aceon®), quinapril (Accupril®), ramipril (Altace®), and trandolapril(Mavik®).

Vasodilators reduce pressure on the blood vessels by making them relaxand expand. Examples of vasodilators include hydralazine, diazoxide,prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassiumchannel activators, and calcium channel blockers also act asvasodilators.

Cardiac glycosides are compounds that increase the force of the heart'scontractions. These compounds strengthen the pumping capacity of theheart and improve irregular heartbeat activity. Examples of cardiacglycosides include digitalis, digoxin, and digitoxin.

Antithrombotic Agents

Antithrombotics inhibit the clotting ability of the blood. There arethree main types of antithrombotics—platelet inhibitors, anticoagulants,and thrombolytic agents.

Platelet inhibitors inhibit the clotting activity of platelets, therebyreducing clotting in the arteries. Examples of platelet inhibitorsinclude acetylsalicylic acid (aspirin), ticlopidine, clopidogrel(Plavix®), prasugrel (Effient®), dipyridamole, cilostazol, persantinesulfinpyrazone, dipyridamole, indomethacin, and glycoprotein llb/lllainhibitors, such as abciximab, tirofiban, and eptifibatide(Integrelin®). Beta blockers and calcium channel blockers also have aplatelet-inhibiting effect.

Anticoagulants prevent blood clots from growing larger and prevent theformation of new clots. Examples of anticoagulants include bivalirudin(Angiomax®), warfarin (Coumadin®), unfractionated heparin, low molecularweight heparin, danaparoid, lepirudin, and argatroban.

Thrombolytic agents act to break down an existing blood clot. Examplesof thrombolytic agents include streptokinase, urokinase, andtenecteplase (TNK), and tissue plasminogen activator (t-PA).

Antiarrhythmic Agents

Antiarrhythmic agents are used to treat disorders of the heart rate andrhythm. Examples of antiarrhythmic agents include amiodarone,dronedarone, quinidine, procainamide, lidocaine, and propafenone.Cardiac glycosides and beta blockers are also used as antiarrhythmicagents.

Combinations with amiodarone and dronedarone are of particular interest(see U.S. Patent Application Publication No. 2010/0056536 and U.S.Patent Application Publication No. 2011/0183990, the entirety of whichare incorporated herein).

Antihypertensive Agents

Antihypertensive agents are used to treat hypertension, a condition inwhich the blood pressure is consistently higher than normal.Hypertension is associated with many aspects of cardiovascular disease,including congestive heart failure, atherosclerosis, and clot formation.Examples of antihypertensive agents include alpha-1-adrenergicantagonists, such as prazosin (Minipress®), doxazosin mesylate(Cardura®), prazosin hydrochloride (Minipress®), prazosin, polythiazide(Minizide®), and terazosin hydrochloride (Hytrin®); beta-adrenergicantagonists, such as propranolol (Inderal®), nadolol (Corgard®), timolol(Blocadren®), metoprolol (Lopressor®), and pindolol (Visken®); centralalpha-adrenoceptor agonists, such as clonidine hydrochloride(Catapres®), clonidine hydrochloride and chlorthalidone (Clorpres®,Combipres®), guanabenz Acetate (Wytensin®), guanfacine hydrochloride(Tenex®), methyldopa (Aldomet®), methyldopa and chlorothiazide(Aldoclor®), methyldopa and hydrochlorothiazide (Aldoril®); combinedalpha/beta-adrenergic antagonists, such as labetalol (Normodyne®,Trandate®), carvedilol (Coreg®); adrenergic neuron blocking agents, suchas guanethidine (Ismelin®), reserpine (Serpasil®); central nervoussystem-acting antihypertensives, such as clonidine (Catapres®),methyldopa (Aldomet®), guanabenz (Wytensin®); anti-angiotensin IIagents; ACE inhibitors, such as perindopril (Aceon®) captopril(Capoten®), enalapril (Vasotec®), lisinopril (Prinivil®, Zestril®);angiotensin-II receptor antagonists, such as candesartan (Atacand®),eprosartan (Tevete®), irbesartan (Avapro®), losartan (Cozaar®),telmisartan (Micardis®), valsartan (Diovan®); calcium channel blockers,such as verapamil (Calan®, Isoptin®), diltiazem (Cardizem®), nifedipine(Adalat®, Procardia®); diuretics; direct vasodilators, such asnitroprusside (Nipride®), diazoxide (Hyperstat® IV), hydralazine(Apresoline®), minoxidil (Loniten®), verapamil; and potassium channelactivators, such as aprikalim, bimakalim, cromakalim, emakalim,nicorandil, and pinacidil.

Lipid Lowering Agents

Lipid lowering agents are used to lower the amounts of cholesterol orfatty sugars present in the blood. Examples of lipid lowering agentsinclude bezafibrate (Bezalip®), ciprofibrate (Modalim®), and statins,such as atorvastatin (Lipitor®), fluvastatin (Lescol®), lovastatin(Mevacor®, Altocor®), mevastatin, pitavastatin (Livalo®, Pitava®)pravastatin (Lipostat®), rosuvastatin (Crestor®), and simvastatin(Zocor).

In this disclosure, the patient presenting with an acute coronarydisease event often suffers from secondary medical conditions such asone or more of a metabolic disorder, a pulmonary disorder, a peripheralvascular disorder, or a gastrointestinal disorder. Such patients canbenefit from treatment of a combination therapy comprising administeringto the patient a compound as disclosed herein (e.g., Formula I, IA, IB,IC or ID) in combination with at least one therapeutic agent.

Pulmonary Disorders Combination Therapy

Pulmonary disorder refers to any disease or condition related to thelungs. Examples of pulmonary disorders include, without limitation,asthma, chronic obstructive pulmonary disease (COPD), bronchitis, andemphysema.

Examples of therapeutics agents used to treat pulmonary disordersinclude bronchodilators including beta2 agonists and anticholinergics,corticosteroids, and electrolyte supplements. Specific examples oftherapeutic agents used to treat pulmonary disorders includeepinephrine, terbutaline (Brethaire®, Bricanyl®), albuterol(Proventil®), salmeterol (Serevent®, Serevent Diskus®), theophylline,ipratropium bromide (Atrovent®), tiotropium (Spiriva®),methylprednisolone (Solu-Medrol®, Medrol®), magnesium, and potassium.

Metabolic Disorders Combination Therapy

Examples of metabolic disorders include, without limitation, diabetes,including type I and type II diabetes, metabolic syndrome, dyslipidemia,obesity, glucose intolerance, hypertension, elevated serum cholesterol,and elevated triglycerides.

Examples of therapeutic agents used to treat metabolic disorders includeantihypertensive agents and lipid lowering agents, as described in thesection “Cardiovascular Agent Combination Therapy” above. Additionaltherapeutic agents used to treat metabolic disorders include insulin,sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretinmimetics.

Peripheral Vascular Disorders Combination Therapy

Peripheral vascular disorders are disorders related to the blood vessels(arteries and veins) located outside the heart and brain, including, forexample peripheral arterial disease (PAD), a condition that developswhen the arteries that supply blood to the internal organs, arms, andlegs become completely or partially blocked as a result ofatherosclerosis.

Gastrointestinal Disorders Combination Therapy

Gastrointestinal disorders refer to diseases and conditions associatedwith the gastrointestinal tract. Examples of gastrointestinal disordersinclude gastroesophageal reflux disease (GERD), inflammatory boweldisease (IBD), gastroenteritis, gastritis and peptic ulcer disease, andpancreatitis.

Examples of therapeutic agents used to treat gastrointestinal disordersinclude proton pump inhibitors, such as pantoprazole (Protonix®),lansoprazole (Prevacid®), esomeprazole (Nexium®), omeprazole(Prilosec®), rabeprazole; H2 blockers, such as cimetidine (Tagamet®),ranitidine (Zantac®), famotidine (Pepcid®), nizatidine (Axid®);prostaglandins, such as misoprostol (Cytotec®); sucralfate; andantacids.

Antibiotics, Analgesics, Antidepressants and Anti-Anxiety AgentsCombination Therapy

Patients presenting with an acute coronary disease event may exhibitconditions that benefit from administration of therapeutic agent oragents that are antibiotics, analgesics, antidepressant and anti-anxietyagents in combination with a compound as disclosed herein (e.g., FormulaI, IA, IB, IC or ID).

Antibiotics

Antibiotics are therapeutic agents that kill, or stop the growth of,microorganisms, including both bacteria and fungi. Example of antibioticagents include β-Lactam antibiotics, including penicillins(amoxicillin), cephalosporins, such as cefazolin, cefuroxime, cefadroxil(Duricee®), cephalexin (Keflex®), cephradine (Velose®), cefaclor(Ceclor®), cefuroxime axtel (Ceftin®), cefprozil (Cefzil®), loracarbef(Lorabid®), cefixime (Suprax®), cefpodoxime proxetil (Vantin®),ceftibuten (Cedax®), cefdinir (Omnicee®), ceftriaxone (Rocephin®),carbapenems, and monobactams; tetracyclines, such as tetracycline;macrolide antibiotics, such as erythromycin; aminoglycosides, such asgentamicin, tobramycin, amikacin; quinolones such as ciprofloxacin;cyclic peptides, such as vancomycin, streptogramins, polymyxins;lincosamides, such as clindamycin; oxazolidinoes, such as linezolid; andsulfa antibiotics, such as sulfisoxazole.

Analgesics

Analgesics are therapeutic agents that are used to relieve pain.Examples of analgesics include opiates and morphinomimetics, such asfentanyl and morphine; paracetamol; NSAIDs, and COX-2 inhibitors. Giventhe ability of the late sodium channel blockers of the disclosure totreat neuropathic pain via inhibition of the Nay 1.7 and 1.8 sodiumchannels, combination with analgesics are particularly invisioned. SeeU.S. Patent Application Publication 20090203707.

Antidepressant and Anti-Anxiety Agents

Antidepressant and anti-anxiety agents include those agents used totreat anxiety disorders, depression, and those used as sedatives andtranquilizers. Examples of antidepressant and anti-anxiety agentsinclude benzodiazepines, such as diazepam, lorazepam, and midazolam;enzodiazepines; barbiturates; glutethimide; chloral hydrate;meprobamate; sertraline (Zoloft®, Lustral®, Apo-Sertral®, Asentra®,Gladem®, Serlift®, Stimuloton®); escitalopram (Lexapro®, Cipralex®);fluoxetine (Prozac®, Sarafem®, Fluctin®, Fontex®, Prodep®, Fludep®,Lovan®); venlafaxine (Effexor® XR, Efexor®); citalopram (Celexa®,Cipramil®, Talohexane®); paroxetine (Paxil®, Seroxat®, Aropax®);trazodone (Desyrel®); amitriptyline (Elavil®); and bupropion(Wellbutrin®, Zyban®).

Accordingly, one aspect of the disclosure provides for a compositioncomprising the late sodium channel blockers of the disclosure and atleast one therapeutic agent. In an alternative embodiment, thecomposition comprises the late sodium channel blockers of the disclosureand at least two therapeutic agents. In further alternative embodiments,the composition comprises the late sodium channel blockers of thedisclosure and at least three therapeutic agents, the late sodiumchannel blockers of the disclosure and at least four therapeutic agents,or the late sodium channel blockers of the disclosure and at least fivetherapeutic agents.

The methods of combination therapy include co-administration of a singleformulation containing the late sodium channel blockers of thedisclosure and therapeutic agent or agents, essentially contemporaneousadministration of more than one formulation comprising the late sodiumchannel blocker of the disclosure and therapeutic agent or agents, andconsecutive administration of a late sodium channel blocker of thedisclosure and therapeutic agent or agents, in any order, whereinpreferably there is a time period where the late sodium channel blockerof the disclosure and therapeutic agent or agents simultaneously exerttheir therapeutic affect.

6. Synthesis of Example Compounds

The compounds of the disclosure may be prepared using methods disclosedherein and routine modifications thereof which will be apparent giventhe disclosure herein and methods well known in the art. Conventionaland well-known synthetic methods may be used in addition to theteachings herein. The synthesis of typical compounds described herein,e.g. compounds having structures described by one or more of Formula I,IA, IB, IC or ID or other formulas or compounds disclosed herein, may beaccomplished as described in the following examples. If available,reagents may be purchased commercially, e.g. from Sigma Aldrich or otherchemical suppliers.

General Syntheses

Typical embodiments of compounds in accordance with the presentdisclosure may be synthesized using the general reaction schemesdescribed below. It will be apparent given the description herein thatthe general schemes may be altered by substitution of the startingmaterials with other materials having similar structures to result inproducts that are correspondingly different. Descriptions of synthesesfollow to provide numerous examples of how the starting materials mayvary to provide corresponding products. Given a desired product forwhich the substituent groups are defined, the necessary startingmaterials generally may be determined by inspection. Starting materialsare typically obtained from commercial sources or synthesized usingpublished methods. For synthesizing compounds which are embodiments ofthe present disclosure, inspection of the structure of the compound tobe synthesized will provide the identity of each substituent group. Theidentity of the final product will generally render apparent theidentity of the necessary starting materials by a simple process ofinspection, given the examples herein.

Synthetic Reaction Parameters

The compounds of this disclosure can be prepared from readily availablestarting materials using, for example, the following general methods andprocedures. It will be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and G. M. Wuts (1999) Protecting Groups inOrganic Synthesis, 3rd Edition, Wiley, New York, and references citedtherein.

Furthermore, the compounds of this disclosure may contain one or morechiral centers. Accordingly, if desired, such compounds can be preparedor isolated as pure stereoisomers, i.e., as individual enantiomers ordiastereomers or as stereoisomer-enriched mixtures. All suchstereoisomers (and enriched mixtures) are included within the scope ofthis disclosure, unless otherwise indicated. Pure stereoisomers (orenriched mixtures) may be prepared using, for example, optically activestarting materials or stereoselective reagents well-known in the art.Alternatively, racemic mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents, and the like.

The starting materials for the following reactions are generally knowncompounds or can be prepared by known procedures or obviousmodifications thereof. For example, many of the starting materials areavailable from commercial suppliers such as Aldrich Chemical Co.(Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemce orSigma (St. Louis, Mo., USA). Others may be prepared by procedures orobvious modifications thereof, described in standard reference textssuch as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15(John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds,Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989)organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March'sAdvanced Organic Chemistry, (John Wiley, and Sons, 5^(th) Edition,2001), and Larock's Comprehensive Organic Transformations (VCHPublishers Inc., 1989).

The terms “solvent,” “inert organic solvent” or “inert solvent” refer toa solvent inert under the conditions of the reaction being described inconjunction therewith (including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, pyridine and the like). Unless specified to the contrary, thesolvents used in the reactions of the present disclosure are inertorganic solvents, and the reactions are carried out under an inert gas,preferably nitrogen.

The term “q.s.” means adding a quantity sufficient to achieve a statedfunction, e.g., to bring a solution to the desired volume (i.e., 100%).

Synthesis of the Compounds of Formula I

The compounds of Formula I (including Formula IA, IB, IC or ID) mayprepared by first providing the benzoisoxazole core, and then attachingthe desired substituents using suitable coupling conditions (e.g.,Suzuki coupling, Mitsunobu reaction, alkylation, etc.). Exemplaryprocesses are show below in Schemes 1 and 2 for the synthesis of acompound of Formula I.

Scheme 1 shows the preparation of compounds of Formula I, where L′comprises a —O— group attached to the benzoisoxazole core, wherein LG isa leaving group (e.g., halo) and alkyl, X, Z, R¹, R², R³, R⁴, p and qare as defined herein.

In Scheme 1, suitably substituted 5-bromo-2-hydroxybenzoate 1-2, whichcan be obtained from the corresponding benzoic acid 1-6 through standardesterification conditions, is coupled with suitably substitutedarylboronic acid or ester in the presence of a palladium catalyst toprovide biaryl ester 1-3. The ester is converted to hydroxamic acid 1-4by heating with hydroxylamine. Hydroxybenzisoxazole 1-5 is obtained bycyclization with carbonyldiimidazole. Alkylation of 1-5 to obtaincompound 1-1 is achieved by reaction with a suitable halide in thepresence of a base such as cesium- or potassium carbonate in DMF oralternately by reaction with an alcohol in the presence of anazodicarboxylate reagent (DIAD, DEAD, etc) and triphenylphosphine underMitsunobu conditions.

Alternately, benzoic acid 1-6 is transformed to the hydroxamic acid 1-7using standard conditions, followed by cyclization to thehydroxybenzisoxazole 1-8. Alkylated product 1-9 is obtained by reactionwith a suitable alkyl halide in the presence of a base such as cesium-or potassium carbonate in DMF or alternately by reaction with an alcoholin the presence of an azodicarboxylate reagent (DIAD, DEAD, etc) andtriphenylphosphine under Mitsunobu conditions. Bromobenzisoxazole 1-9 isthen converted to compound 1-1 by coupling with a suitably substitutedarylboronic acid or ester in the presence of a palladium catalyst understandard Suzuki coupling conditions. Each of the intermediates in theabove scheme may be isolated and/or purified prior to the subsequentstep, or used in the next step without isolation.

Schemes 2 and 3 show the preparation of compounds of Formula I, where L¹comprises a —NH— group attached to the benzoisoxazole core or Y is ahetercyclic or heteroaryl ring. In Schemes 2 and 3, LG is a leavinggroup (e.g., halo) and Z, X, R¹, R², R³, R⁴, p and q are as definedherein.

In Scheme 2, chlorobenzisoxazole 2-1 is converted to compound 2-2 bycoupling with a suitably substituted arylboronic acid or ester in thepresence of a palladium catalyst under standard Suzuki couplingconditions. Compound 2-2 may be isolated and/or purified, or used in thenext step without isolation. Amination of 2-2 to obtain compounds 2-3and 2-4 is achieved by reaction with a suitable amine in the presence ofa base such as diazabicyclo[5.4.0]undec-7-ene. The reaction may befacilitated by use of a microwave reactor.

In Scheme 3, aminobenzisoxazole 3-1 is converted to compound 3-2 bycoupling with a suitably substituted arylboronic acid or ester in thepresence of a palladium catalyst under standard Suzuki couplingconditions. Compound 3-2 may be isolated and/or purified, or used in thenext step without isolation. Alkylation of 3-2 to obtain 3-3 is achievedby reaction with a suitable carbonyl-containing compound under standardreductive amination conditions, typically with the use of a drying agentfollowed by the addition of a reducing agent, such as sodiumborohydride.

It will also be appreciated that the addition of any substituent mayresult in the production of a number of isomeric products any or all ofwhich may be isolated and purified using conventional techniques.

EXAMPLES

The following examples are included to demonstrate preferred embodimentsof the disclosure. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the disclosure, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe disclosure.

List of abbreviations and acronyms. Abbreviation Meaning ° C. DegreeCelcius anal Analytical ATP Adenosine-5′-triphosphate ATX II Anemoniasulcata toxin ACN Acetonitrile CHO Chinese hamster ovary conc.Concentrated d Doublet DABCO 1,4-Diazabicyclo[2.2.2]octane dd Doublet ofdoublets DCM Dichloromethane DIPEA N,N-diisopropylethylamine DMFDimethylformamide DMSO Dimethylsulfoxide dppf1,1′-Bis(diphenylphosphino)ferrocene EA Ethyl alcohol ECF Extracellularfluid EDTA Ethylenediaminetetraacetic acid EGTA Ethylene glycoltetraacetic acid equiv/eq Equivalents ESI Electrospray ionization AcAcetate Et Ethyl g Grams HEPES(4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid) HATU2-(7-Aza-1H-Benzotriazole-1-yl)-1,1,3,3- tetramethyluroniumhexafluorophosphate hERG human Ether-a-go-go Related Gene HPLCHigh-performance liquid chromatography h Hours Hz Hertz IC₅₀ The halfmaximal inhibitory concentration IMR-32 Human neuroblastoma cell line JCoupling constant Kg Kilogram kHz Kilohertz LCMS/LC-MS Liquidchromatography-mass spectrometry M Molar m multiplet m/z mass-to-chargeratio M+ Mass peak M + H Mass peak plus hydrogen Me Methyl mg MilligramMHz Megahertz min/m Minute ml/mL Milliliter mM Millimolar mmol Millimolenmol Nanomole mOsmol Milliosmole MRM Magnetic Resonance Microscopy MSMass spectroscopy ms Millisecond mV Millivolt mw Microwave N Normal molMole NMR Nuclear magnetic resonance pA Picoamps Ph Phenyl prepPreparative q.s. Quantity sufficient to achieve a stated function RfRetention factor RT/rt Room temperature s Second s Singlet SEM Standarderror of the mean t Triplet TB Tonic Block TEA Triethylamine TFATrifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatographyTTX Tetrodotoxin UDB Use Dependent Block WT Wild type δ Chemical shiftμg Microgram μL/μl Microliter μM Micromolar μm Micrometer μmol Micromole

Example 13-(pyrimidin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

Step 1: Methyl 5-bromosalicylate (5 g, 21.6 mmol) was dissolved in 90 mL1,4-dioxane and 10 mL water. 10 mL 50% aqueous hydroxylamine solutionwas added and the mixture was stirred at ambient temperature for 24hours. After concentrating the mixture under vacuum, water was added.The formed precipitate was filtered, washed with water and driedyielding 5-bromo-N,2-dihydroxybenzamide (4.12 g, 17.76 mmol) asoff-white solid.

Step 2: 5-bromo-N,2-dihydroxybenzamide (4.12 g, 17.76 mmol) wassuspended in 100 mL THF. Carbonyldiimidazole (5.76 g, 35.5 mmol) wasadded and the mixture was heated under reflux for three hours. Thesolvent was evaporated under vacuum, 100 mL water was added and thesolution was acidified to pH 1 with 1N HCl under rapid stirring. Theformed precipitate was filtered, washed with water and dried, giving5-bromobenzo[d]isoxazol-3-ol (3.71 g, 17.3 mmol) as off-white solid.

Step 3: 5-bromobenzo[d]isoxazol-3-ol (200 mg, 0.93 mmol),2-(chloromethyl)pyrimidine hydrochloride (200 mg, 1.21 mmol) and cesiumcarbonate (1 g) were combined in 10 mL DMF and stirred at ambienttemperature for two days. The reaction mixture was diluted with 60 mLethyl acetate, washed with water and brine and evaporated under vacuum.Flash chromatographic purification on 12 g silica gel with 0-100% ethylacetate in hexane gave O-alkylated product5-bromo-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole (120 mg, 0.39 mmol).

Step 4: 5-Bromo-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole (120 mg, 0.39mmol), 4-(trifluoromethoxy)phenylboronic acid (120 mg, 0.58 mmol),potassium carbonate (500 mg), and[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (25 mg,0.034 mmol) were combined in 6 mL DMF. 3 mL water was added and themixture was stirred at 80° C. for two hours. The reaction mixture wasdiluted with 60 mL ethyl acetate, washed with water and brine andevaporated under vacuum. Flash chromatographic purification on 12 gsilica gel with 0-60% ethyl acetate in hexane gave3-(pyrimidin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole(94 mg, 0.24 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (d, J=4.9 Hz, 2H), 8.07-8.01 (m, 1H),7.97 (dd, J=8.8, 1.8 Hz, 1H), 7.91-7.83 (m, 2H), 7.72 (d, J=8.8 Hz, 1H),7.51-7.40 (m, 3H), 5.67 (s, 2H). MS: 388 (MH⁺).

The following compounds were synthesized using the above procedure,substituting with the appropriate boronic acid.

Example 25-(2-fluoro-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (d, J=4.9 Hz, 2H), 7.98-7.93 (m, 1H),7.84 (dt, J=8.8, 1.7 Hz, 1H), 7.80-7.71 (m, 2H), 7.58-7.50 (m, 1H), 7.47(t, J=4.9 Hz, 1H), 7.39-7.31 (m, 1H), 5.67 (s, 2H). MS: 406 (MH⁺).

Example 35-(2-methyl-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (d, J=4.9 Hz, 2H), 7.75-7.71 (m, 1H),7.69 (d, 1H), 7.64 (dd, J=8.7, 1.7 Hz, 1H), 7.47 (t, J=4.9 Hz, 1H), 7.38(d, J=8.4 Hz, 1H), 7.36-7.31 (m, 1H), 7.29-7.22 (m, 1H), 5.66 (s, 2H),2.25 (s, 3H). MS: 402 (MH⁺).

Example 45-(2-methoxy-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (d, J=4.9 Hz, 2H), 7.84-7.79 (m, 1H),7.74 (dd, J=8.8, 1.7 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.52-7.43 (m, 2H),7.16-7.11 (m, 1H), 7.07-6.98 (m, 1H), 5.66 (s, 2H), 3.81 (s, 3H). MS:418 (MH⁺).

Example 53-((4-methylpyrimidin-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.65 (d, J=5.1 Hz, 1H), 8.05 (dd, J=1.9, 0.8Hz, 1H), 7.97 (dd, J=8.8, 1.9 Hz, 1H), 7.92-7.83 (m, 2H), 7.73 (dd,J=8.8, 0.7 Hz, 1H), 7.44 (d, J=7.6 Hz, 2H), 7.35 (d, J=5.1 Hz, 1H), 5.60(s, 2H), 2.46 (s, 3H). MS: 402 (MH⁺).

Example 65-(2-fluoro-4-(trifluoromethyl)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J=4.9 Hz, 2H), 8.01 (t, J=1.4 Hz,1H), 7.91-7.84 (m, 2H), 7.82 (dd, J=10.8, 1.7 Hz, 1H), 7.77 (d, J=8.9Hz, 1H), 7.68 (dd, J=8.2, 1.7 Hz, 1H), 7.47 (t, J=4.9 Hz, 1H), 5.67 (s,2H). m/z: 390 (MH+)

Example 75-(3-methyl-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J=4.9 Hz, 2H), 8.04 (d, J=1.7 Hz,1H), 7.97 (dd, J=8.8, 1.9 Hz, 1H), 7.81 (d, J=2.3 Hz, 1H), 7.71 (d,J=8.8 Hz, 1H), 7.68 (dd, J=8.5, 2.5 Hz, 1H), 7.48 (t, J=4.9 Hz, 1H),7.37 (dt, J=8.5, 1.6 Hz, 1H), 5.66 (s, 2H), 2.34 (s, 3H). m/z: 402(MH⁺).

Example 85-(4-chloro-3-fluorophenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J=4.9 Hz, 2H), 8.13 (d, J=1.7 Hz,1H), 8.02 (dd, J=8.8, 1.9 Hz, 1H), 7.92-7.85 (m, 1H), 7.73 (d, J=8.8 Hz,1H), 7.67-7.64 (m, 2H), 7.48 (t, J=4.9 Hz, 1H), 5.67 (s, 2H). m/z: 356(MH+)

Example 93-(pyrimidin-2-ylmethoxy)-5-(4-(trifluoromethyl)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J=4.9 Hz, 2H), 8.15 (d, J=1.7 Hz,1H), 8.05 (dd, J=8.8, 1.8 Hz, 1H), 8.01 (d, J=8.1 Hz, 2H), 7.83 (d,J=8.2 Hz, 2H), 7.78 (d, J=8.8 Hz, 1H), 7.50 (t, J=4.9 Hz, 1H), 5.70 (s,2H). m/z: 372 (MH+)

Example 103-(pyrimidin-2-ylmethoxy)-5-(3-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J=4.9 Hz, 2H), 8.10 (d, J=1.7 Hz,1H), 8.01 (dd, J=8.8, 1.9 Hz, 1H), 7.81 (ddd, J=7.9, 1.9, 1.0 Hz, 1H),7.78-7.75 (m, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.48(t, J=4.9 Hz, 1H), 7.40-7.33 (m, 1H), 5.67 (s, 2H). m/z: 388 (MH+)

Example 116-methoxy-3-(pyrimidin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J=4.9 Hz, 2H), 7.56-7.48 (m, 2H),7.42 (t, J=4.9 Hz, 1H), 7.39-7.32 (m, 3H), 7.24 (s, 1H), 5.27 (s, 2H),3.77 (s, 3H). m/z: 418 (MH+).

Example 125-(2-fluoro-4-(trifluoromethyl)phenyl)-6-methoxy-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J=4.9 Hz, 2H), 7.69 (dd, J=9.9, 1.7Hz, 1H), 7.62-7.57 (m, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.42 (t, J=4.9 Hz,1H), 7.39 (s, 1H), 7.21 (s, 1H), 5.25 (s, 2H), 3.76 (s, 3H). m/z: 420(MH⁺).

Example 135-(4-chloro-3-fluorophenyl)-6-methoxy-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J=4.9 Hz, 2H), 7.57 (t, J=8.2 Hz,1H), 7.46 (dd, J=11.0, 2.0 Hz, 1H), 7.42 (t, J=4.9 Hz, 1H), 7.35 (s,1H), 7.32-7.26 (m, 2H), 5.28 (s, 2H), 3.78 (s, 3H). m/z: 386 (MH+)

Example 146-methoxy-5-(3-methyl-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J=4.9 Hz, 2H), 7.50 (t, J=4.9 Hz,1H), 7.48 (d, J=2.1 Hz, 1H), 7.44-7.40 (m, 2H), 7.37 (dd, J=8.5, 1.5 Hz,1H), 7.31 (s, 1H), 5.36 (s, 2H), 3.85 (s, 3H), 2.35 (s, 3H). m/z: 432(MH+)

Example 155-(3-chloro-4-fluorophenyl)-6-methoxy-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J=4.9 Hz, 2H), 7.61-7.56 (m, 1H),7.44-7.39 (m, 3H), 7.34 (s, 1H), 7.27 (s, 1H), 5.28 (s, 2H), 3.77 (s,3H). m/z: 386 (MH⁺).

Example 167-methyl-3-(pyrimidin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J=4.9 Hz, 2H), 7.88-7.83 (m, 3H),7.81 (t, J=1.4 Hz, 1H), 7.47 (t, J=4.9 Hz, 1H), 7.44 (d, J=8.5 Hz, 2H),5.66 (s, 2H), 2.49 (s, 3H). m/z: 402 (MH⁺).

Example 177-fluoro-3-(pyrimidin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J=4.9 Hz, 2H), 8.01 (dd, J=12.2,1.5 Hz, 1H), 7.97-7.89 (m, 3H), 7.54-7.40 (m, 3H), 5.69 (s, 2H). m/z:406 (MH⁺).

Example 187-methyl-5-(3-methyl-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J=4.9 Hz, 2H), 7.93 (d, J=1.8 Hz,1H), 7.90-7.82 (m, 2H), 7.67-7.63 (m, 2H), 7.48 (t, J=4.9 Hz, 1H), 5.66(s, 2H), 2.49 (s, 3H), 2.48 (s, 3H). m/z: 416 (MH⁺).

Example 197-methyl-3-(pyrimidin-2-ylmethoxy)-5-(3-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J=5.0 Hz, 2H), 7.93-7.89 (m, 1H),7.86 (dd, J=1.8, 1.0 Hz, 1H), 7.83-7.78 (m, 1H), 7.75 (s, 1H), 7.59 (t,J=8.0 Hz, 1H), 7.48 (t, J=4.9 Hz, 1H), 7.40-7.32 (m, 1H), 5.66 (s, 2H),2.50 (s, 3H). m/z: 402 (MH⁺).

Example 205-(6-cyclopropylpyridin-3-yl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J=4.9 Hz, 2H), 8.76 (dd, J=2.5, 0.8Hz, 1H), 8.05 (dd, J=1.9, 0.7 Hz, 1H), 8.01 (dd, J=8.2, 2.5 Hz, 1H),7.97 (dd, J=8.8, 1.9 Hz, 1H), 7.72 (dd, J=8.8, 0.7 Hz, 1H), 7.48 (t,J=4.9 Hz, 1H), 7.37 (dd, J=8.2, 0.8 Hz, 1H), 5.67 (s, 2H), 2.14 (tt,J=7.7, 5.2 Hz, 1H), 1.00-0.93 (m, 4H). m/z: 345 (MH⁺).

Example 213-(pyrimidin-2-ylmethoxy)-5-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J=4.9 Hz, 2H), 8.58 (dd, J=2.6, 0.8Hz, 1H), 8.21 (dd, J=8.6, 2.6 Hz, 1H), 8.07 (dd, J=1.8, 0.8 Hz, 1H),7.98 (dd, J=8.8, 1.9 Hz, 1H), 7.73 (dd, J=8.8, 0.7 Hz, 1H), 7.48 (t,J=4.9 Hz, 1H), 7.08 (dd, J=8.6, 0.7 Hz, 1H), 5.67 (s, 2H), 5.04 (q,J=9.1 Hz, 2H). m/z: 403 (MH⁺).

Example 227-methoxy-3-(pyrimidin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J=4.9 Hz, 2H), 7.94-7.85 (m, 2H),7.55 (d, J=1.4 Hz, 1H), 7.51-7.40 (m, 4H), 5.66 (s, 2H), 4.04 (s, 3H).m/z: 418 (MH⁺).

Example 237-methoxy-5-(3-methyl-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J=4.9 Hz, 2H), 7.83 (d, J=2.3 Hz,1H), 7.71 (dd, J=8.5, 2.4 Hz, 1H), 7.55 (d, J=1.4 Hz, 1H), 7.51-7.45 (m,2H), 7.37 (dt, J=8.5, 1.5 Hz, 1H), 5.65 (s, 2H), 4.04 (s, 3H), 2.35 (s,3H). m/z: 432 (MH⁺).

Example 245-(2-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J=4.9 Hz, 2H), 7.89 (t, J=7.9 Hz,1H), 7.86-7.79 (m, 1H), 7.72-7.66 (m, 1H), 7.52 (t, J=1.5 Hz, 1H), 7.47(t, J=4.9 Hz, 1H), 7.42 (t, J=1.3 Hz, 1H), 5.66 (s, 2H), 4.01 (s, 3H).m/z: 420 (MH⁺).

Example 257-methoxy-5-(2-methyl-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J=4.9 Hz, 2H), 7.47 (t, J=4.9 Hz,1H), 7.40 (d, J=8.4 Hz, 1H), 7.36-7.31 (m, 1H), 7.28-7.23 (m, 1H), 7.22(d, J=1.3 Hz, 1H), 7.18 (d, J=1.3 Hz, 1H), 5.64 (s, 2H), 3.96 (s, 3H),2.28 (s, 3H). m/z: 432 (MH⁺).

Example 266-methyl-3-(pyrimidin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J=4.9 Hz, 2H), 7.61-7.58 (m, 1H),7.56 (s, 1H), 7.54-7.49 (m, 2H), 7.49-7.40 (m, 3H), 5.63 (s, 2H), 2.31(s, 3H). m/z: 402 (MH+)

Example 276-methyl-5-(3-methyl-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J=4.9 Hz, 21-1), 7.62-7.57 (m, 1H),7.55 (s, 1H), 7.47 (t, J=4.9 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.37 (dd,J=8.3, 1.5 Hz, 1H), 7.33 (dd, J=8.4, 2.1 Hz, 1H), 5.63 (s, 2H), 2.32 (s,6H). m/z: 416 (MH+)

Example 285-(2-fluoro-4-(trifluoromethyl)phenyl)-6-methyl-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J=4.9 Hz, 2H), 7.82 (dd, J=9.8, 1.4Hz, 1H), 7.73-7.60 (m, 4H), 7.46 (t, J=4.9 Hz, 1H), 5.64 (s, 2H), 2.23(s, 3H). m/z: 404 (MH+)

Example 296-methyl-5-(2-methyl-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J=4.9 Hz, 2H), 7.63-7.58 (m, 1H),7.49-7.43 (m, 2H), 7.35 (s, 1H), 7.24 (s, 2H), 5.62 (s, 2H), 2.08 (s,3H), 2.02 (s, 3H). m/z: 416 (MH+)

Example 305-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J=4.9 Hz, 2H), 8.07-8.02 (m, 1H),7.96 (dd, J=8.8, 1.8 Hz, 1H), 7.87 (d, J=1.7 Hz, 1H), 7.72 (d, J=8.8 Hz,1H), 7.59 (dd, J=8.4, 1.8 Hz, 1H), 7.52-7.45 (m, 2H), 5.67 (s, 2H). m/z:384 (MH+)

Example 316-fluoro-3-(pyrimidin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J=4.9 Hz, 2H), 7.95 (d, J=7.4 Hz,1H), 7.80 (d, J=10.5 Hz, 1H), 7.76-7.69 (m, 2H), 7.52-7.44 (m, 3H), 5.65(s, 2H). m/z: 406 (MH+)

Example 326-fluoro-5-(3-methyl-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J=4.9 Hz, 2H), 7.94 (d, J=7.3 Hz,1H), 7.79 (d, J=10.4 Hz, 1H), 7.64 (s, 1H), 7.53 (dt, J=8.6, 2.1 Hz,1H), 7.48 (t, J=4.9 Hz, 1H), 7.41 (dd, J=8.4, 1.7 Hz, 1H), 5.65 (s, 2H),2.33 (s, 3H). m/z: 420 (MH+)

Example 336-fluoro-5-(2-fluoro-4-(trifluoromethyl)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J=4.9 Hz, 2H), 8.02 (d, J=6.9 Hz,1H), 7.89-7.83 (m, 2H), 7.81 (t, J=7.6 Hz, 1H), 7.75-7.70 (m, 1H), 7.48(t, J=4.9 Hz, 1H), 5.66 (s, 2H). m/z: 408 (MH+)

Example 346-fluoro-5-(2-methyl-4-(trifluoromethoxy)phenyl)-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J=4.9 Hz, 2H), 7.79 (s, 1H), 7.77(d, J 3.6 Hz, 1H), 7.47 (t, J=4.9 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H),7.38-7.35 (m, 1H), 7.31-7.24 (m, 1H), 5.64 (s, 2H), 2.16 (s, 3H). m/z:420 (MH+)

Example 355-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-6-fluoro-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J=4.9 Hz, 2H), 7.93 (d, J=7.4 Hz,1H), 7.79 (d, J=10.4 Hz, 1H), 7.69 (t, J=1.5 Hz, 1H), 7.52 (d, J=8.4 Hz,1H), 7.48 (t, J=4.9 Hz, 1H), 7.42 (dt, J=8.4, 1.7 Hz, 1H), 5.65 (s, 2H).m/z: 402 (MH+)

Example 363-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methoxy)-5-(2-methyl-4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 7.76-7.70 (m, 2H), 7.66 (dd, J=8.7, 1.8 Hz,1H), 7.37 (d, J=8.4 Hz, 1H), 7.35-7.32 (m, 1H), 7.28-7.21 (m, 1H), 5.70(s, 2H), 2.30-2.25 (m, 1H), 2.23 (s, 3H), 1.19-1.11 (m, 2H), 1.04-0.96(m, 2H). m/z: 432 (MH+)

Example 373-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methoxy)-5-(4-(trifluoromethyl)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.12 (dd, J=1.8, 0.8 Hz, 1H), 8.06 (dd,J=8.9, 1.9 Hz, 1H), 8.01-7.95 (m, 2H), 7.84-7.77 (m, 3H), 5.72 (s, 2H),2.28 (tt, J=8.4, 4.9 Hz, 1H), 1.20-1.12 (m, 2H), 1.05-0.97 (m, 2H). m/z:402 (MH+)

Example 383-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methoxy)-5-(2-fluoro-4-(trifluoromethyl)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 7.99 (dt, J=1.9, 1.0 Hz, 1H), 7.90 (dt,J=8.8, 1.7 Hz, 1H), 7.87-7.77 (m, 3H), 7.71-7.63 (m, 1H), 5.71 (s, 2H),2.27 (tt, J=8.4, 4.9 Hz, 1H), 1.18-1.11 (m, 2H), 1.04-0.97 (m, 2H). m/z:420 (MH+)

Example 393-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methoxy)-5-(2-methoxy-4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 7.80-7.74 (m, 2H), 7.69 (dd, J=8.7, 0.9 Hz,1H), 7.46 (d, J=8.4 Hz, 1H), 7.14-7.10 (m, 1H), 7.04-6.98 (m, 1H), 5.69(s, 2H), 3.80 (s, 3H), 2.26 (tt, J=8.4, 4.9 Hz, 1H), 1.18-1.11 (m, 2H),1.04-0.97 (m, 2H). m/z: 448 (MH+)

Example 403-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methoxy)-5-(3-methyl-4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.04 (dd, J=1.9, 0.8 Hz, 1H), 8.00 (dd,J=8.8, 1.9 Hz, 1H), 7.82-7.79 (m, 1H), 7.76 (dd, J=8.8, 0.8 Hz, 1H),7.71-7.64 (m, 1H), 7.37 (dd, J=8.5, 1.7 Hz, 1H), 5.71 (s, 2H), 2.34 (s,3H), 2.28 (tt, J=8.4, 4.9 Hz, 1H), 1.19-1.12 (m, 2H), 1.05-0.98 (m, 2H).m/z: 432 (MH+)

Example 413-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methoxy)-5-(2-fluoro-4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 7.96-7.91 (m, 1H), 7.86 (dt, J=8.8, 1.7 Hz,1H), 7.79 (dd, J=8.7, 0.8 Hz, 1H), 7.75 (t, J=8.8 Hz, 1H), 7.56-7.50 (m,1H), 7.38-7.31 (m, 1H), 5.71 (s, 2H), 2.27 (tt, J=8.4, 4.9 Hz, 1H),1.18-1.11 (m, 2H), 1.04-0.98 (m, 2H). m/z: 436 (MH+)

Example 423-(oxetan-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

Step 1: Diisopropylazodicarboxylate (0.38 mL, 0.70 mmol) was added understirring to a solution of 5-bromobenzo[d]isoxazol-3-ol (100 mg, 0.47mmol), triphenylphosphine (184 mg, 0.70 mmol), and oxetan-2-ylmethanol(62 mg, 0.70 mmol) in THF. The reaction mixture was stirred at ambienttemperature overnight. Volatiles were evaporated under vacuum and theresidue was purified on 12 g silica gel with 0-100% ethyl acetate inhexane and gave 5-bromo-3-(oxetan-2-ylmethoxy)benzo[d]isoxazole (114 mg,0.40 mmol).

Step 2: 5-Bromo-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole (114 mg, 0.40mmol), 4-(trifluoromethoxy)phenylboronic acid (100 mg, 0.49 mmol),potassium carbonate (500 mg), and[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (25 mg,0.034 mmol) were combined in 3 mL DMF. 1.5 mL water was added and themixture was stirred at 60° C. for 30 minutes. The reaction mixture wasdiluted with 60 mL ethyl acetate, washed with water and brine andevaporated under vacuum. Flash chromatographic purification on 12 gsilica gel with 0-60% ethyl acetate in hexane gave the title compound(115 mg, 0.31 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 8.04-7.99 (m, 1H), 7.97 (dd, J=8.8, 1.9 Hz,1H), 7.91-7.82 (m, 2H), 7.73 (d, J=8.8 Hz, 1H), 7.44 (d, J=8.2 Hz, 2H),5.16-5.06 (m, 1H), 4.65-4.49 (m, 4H), 2.81-2.68 (m, 1H), 2.68-2.56 (m,1H). MS: 366 (MH⁺).

Example 433-((1-methyl-1H-imidazol-4-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

Step 1: Methyl 5-bromosalicylate (5 g, 21.6 mmol),4-(trifluoromethoxy)phenylboronic acid (4.43 g, 21.6 mmol), potassiumcarbonate (10 g) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (800 mg,1.09 mmol) were combined in 10 mL DMF. 5 mL water was added and themixture was stirred at 50° C. for 60 minutes. The reaction mixture wasdiluted with 300 mL ethyl acetate, washed with water and brine andevaporated under vacuum. Flash chromatographic purification on 120 gsilica gel with 0-100% ethyl acetate in hexane gave methyl4-hydroxy-4′-(trifluoromethoxy)-[1,1′-biphenyl]-3-carboxylate (5.7 g,18.3 mmol).

Step 2: A solution of4-hydroxy-4′-(trifluoromethoxy)-[1,1′-biphenyl]-3-carboxylate (5.7 g,18.3 mmol) in 10 mL 1,4-dioxane was added to a mixture of 10 mL 50%aqueous KOH and 10 mL 50% aqueous hydroxylamine over 10 minutes. Thereaction mixture was stirred at ambient temperature for 4 hours. Afteracidifying with concentrated HCl, the formed precipitate was filtered,washed with water and dried.

Step 3: The precipitate from Step 2 was dissolved in 50 mL THF.Carbonyldiimidazole (6.23 g, 38.4 mmol) was added and stirred for 10minutes. 12 mL triethylamine was added and the mixture was heated atreflux for two hours. After cooling, the volatiles were removed undervacuum. To the residue was added 50 mL water and the pH was adjusted topH 1 with 1N HCl. The formed precipitate was filtered, washed with waterand dried giving 5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-ol(4.5 g, 15.2 mmol) as a tan solid.

Step 4: Diisopropylazodicarboxylate 40% solution in toluene (0.27 mL,0.51 mmol) was added under stirring to a solution of5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-ol (100 mg, 0.34 mmol),triphenylphosphine on resin (3 mmol/g) (330 mg, 1 mmol), and1-methylimidazol-4-yl methanol (60 mg, 0.51 mmol) in THF. The reactionmixture was stirred at ambient temperature overnight. Volatiles wereevaporated under vacuum and the residue was purified on 12 g silica gelwith 0-20% methanol in dichloromethane and gave the title compound (40mg, 0.103 mmol) as yellowish oil.

¹H NMR (400 MHz, DMSO-d₆) δ 8.07-7.97 (m, 2H), 7.89-7.81 (m, 2H), 7.54(d, J=8.7 Hz, 1H), 7.50-7.41 (m, 3H), 7.12 (d, J=1.3 Hz, 1H), 5.03 (s,2H), 3.59 (s, 3H). MS: 390 (MH⁺).

The following compounds were synthesized using the same procedure butsubstituting the appropriate alcohol in Step 4:

Example 443-((1-methyl-1H-imidazol-4-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (s, 1H), 8.01-7.91 (m, 2H), 7.90-7.79(m, 2H), 7.79-7.71 (m, 1H), 7.46-7.39 (m, 2H), 5.54 (s, 2H), 4.06 (s,3H). MS: 391 (MH⁺).

Example 453-((1H-pyrazol-4-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 12.93 (s, 1H), 8.00-7.92 (m, 3H), 7.90-7.81(m, 2H), 7.76-7.66 (m, 2H), 7.46-7.38 (m, 2H), 5.39 (s, 2H). MS: 376(MH⁺).

Example 464-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)pyrrolidin-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 8.01-7.93 (m, 2H), 7.90-7.81 (m, 2H), 7.73(dd, J=8.6, 0.9 Hz, 1H), 7.61 (s, 1H), 7.49-7.41 (m, 2H), 4.47-4.39 (m,2H), 3.44 (t, J=9.5, 8.4 Hz, 1H), 3.17 (dd, J=9.9, 5.7 Hz, 1H),3.06-2.90 (m, 1H), 2.35 (dd, J=16.7, 9.0 Hz, 1H), 2.14 (dd, J=16.7, 6.9Hz, 1H). MS: 393 (MH⁺).

Example 473-((1-ethyl-1H-imidazol-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.02-7.94 (m, 2H), 7.90-7.81 (m, 2H), 7.76(d, J=9.3 Hz, 1H), 7.46-7.39 (m, 2H), 7.33 (d, J=1.1 Hz, 1H), 6.95 (d,J=1.1 Hz, 1H), 5.52 (s, 2H), 4.10 (q, J=7.3 Hz, 2H), 1.35 (t, J=7.2 Hz,3H). MS: 404 (MH⁺).

Example 483-((1-isopropyl-1H-imidazol-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.03-7.93 (m, 2H), 7.89-7.80 (m, 2H),7.80-7.72 (m, 1H), 7.46-7.39 (m, 3H), 7.00-6.94 (m, 1H), 5.54 (s, 2H),4.60 (p, J=6.5 Hz, 1H), 1.40 (d, J=6.6 Hz, 6H). MS: 418 (MH⁺).

Example 493-((1-ethyl-1H-imidazol-5-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.01-7.61 (m, 5H), 7.49-7.39 (m, 3H), 7.15(s, 1H), 5.52 (s, 2H), 4.08 (q, J=7.3 Hz, 2H), 1.37 (t, J=7.3 Hz, 3H).MS: 404 (MH⁺).

Example 503-((1-methyl-1H-imidazol-5-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.01 (dd, J=1.8, 0.8 Hz, 1H), 7.97 (dd,J=8.8, 1.9 Hz, 1H), 7.90-7.81 (m, 2H), 7.74 (dd, J=8.8, 0.8 Hz, 1H),7.71 (d, J=1.0 Hz, 1H), 7.49-7.39 (m, 2H), 7.14 (d, J=1.0 Hz, 1H), 5.52(s, 2H), 3.71 (s, 3H). MS: 390 (MH⁺).

Example 513-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (dt, J=6.8, 1.1 Hz, 1H), 8.15 (s, 1H),8.00-7.93 (m, 2H), 7.89-7.81 (m, 2H), 7.74 (dd, J=8.6, 1.0 Hz, 1H), 7.54(dt, J=9.2, 1.1 Hz, 1H), 7.42 (dd, J=8.5, 1.4 Hz, 2H), 7.26 (ddd, J=8.9,6.7, 1.2 Hz, 1H), 6.90 (td, J=6.8, 1.1 Hz, 1H), 5.58 (s, 2H). MS: 426(MH⁺).

Example 523-((2,5-dimethyloxazol-4-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.00-7.92 (m, 2H), 7.90-7.82 (m, 2H), 7.72(d, J=9.3 Hz, 1H), 7.42 (dd, J=8.8, 1.3 Hz, 2H), 5.29 (s, 2H), 2.37 (s,3H), 2.34 (s, 3H). MS: 405 (MH⁺).

Example 533-(oxazol-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.23 (d, J=0.8 Hz, 1H), 8.05-8.01 (m, 1H),7.99 (dd, J=8.8, 1.9 Hz, 1H), 7.91-7.83 (m, 2H), 7.76 (d, J=8.8 Hz, 1H),7.43 (dd, J=8.8, 1.2 Hz, 2H), 7.32 (d, J=0.8 Hz, 1H), 5.62 (s, 2H). MS:377 (MH⁺).

Example 542-(1-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)cyclopropyl)acetonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 8.05-8.00 (m, 1H), 7.97 (dd, J=8.8, 1.9 Hz,1H), 7.89-7.81 (m, 2H), 7.73 (d, J=8.7 Hz, 1H), 7.51-7.42 (m, 2H), 4.35(s, 2H), 2.87 (s, 2H), 0.87-0.79 (m, 2H), 0.75-0.68 (m, 2H). MS: 389(MH⁺).

Example 553-(2-(1H-imidazol-1-yl)ethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.00 (dd, J=1.8, 0.8 Hz, 1H), 7.96 (dd,J=8.8, 1.9 Hz, 1H), 7.89-7.80 (m, 2H), 7.78-7.69 (m, 2H), 7.50-7.42 (m,2H), 7.31 (t, J=1.2 Hz, 1H), 6.88 (t, J=1.0 Hz, 1H), 4.67 (t, J=4.9 Hz,2H), 4.48 (t, J=4.9 Hz, 2H). MS: 390 (MH⁺).

Example 561-methyl-4-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)pyrrolidin-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 8.00-7.93 (m, 2H), 7.90-7.79 (m, 2H),7.77-7.69 (m, 1H), 7.49-7.41 (m, 2H), 4.47-4.37 (m, 2H), 3.54 (dd,J=10.0, 8.1 Hz, 1H), 3.31-3.24 (m, 1H), 2.92 (hept, J=6.7 Hz, 1H), 2.72(s, 3H), 2.48-2.40 (m, 1H), 2.23 (dd, J=16.8, 6.6 Hz, 1H). MS: 407(MH⁺).

Example 573-(2-(2-methyl-1H-imidazol-1-yl)ethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (dd, J=8.8, 1.9 Hz, 1H), 7.93-7.87 (m,1H), 7.87-7.79 (m, 2H), 7.73 (dd, J=8.6, 0.9 Hz, 1H), 7.46 (dd, J=8.4,1.3 Hz, 2H), 7.19 (d, J=1.3 Hz, 1H), 6.71 (d, J=1.3 Hz, 1H), 4.67 (t,J=4.9 Hz, 2H), 4.39 (t, J=5.0 Hz, 2H), 2.33 (s, 3H). MS: 404 (MH⁺).

Example 583-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.66 (s, 1H), 7.99 (s, 1H), 7.95 (dd, J=8.8,1.9 Hz, 1H), 7.93-7.88 (m, 1H), 7.89-7.79 (m, 2H), 7.72 (dd, J=8.8, 0.8Hz, 1H), 7.49-7.40 (m, 2H), 4.82-4.69 (m, 4H). MS: 391 (MH⁺).

Example 591-(2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)ethyl)pyrrolidin-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 7.96 (dd, J=8.8, 1.9 Hz, 1H), 7.93-7.89 (m,1H), 7.89-7.80 (m, 2H), 7.73 (dd, J=8.7, 0.8 Hz, 1H), 7.50-7.42 (m, 2H),4.54 (t, J=5.3 Hz, 2H), 3.67 (t, J=5.3 Hz, 2H), 3.49 (t, J=7.0 Hz, 2H),2.19 (dd, J=8.6, 7.5 Hz, 2H), 1.91 (tt, J=7.8, 6.7 Hz, 2H). MS: 407(MH⁺).

Example 603-(2-methoxyethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.00-7.90 (m, 2H), 7.91-7.82 (m, 2H),7.76-7.69 (m, 1H), 7.48-7.39 (m, 2H), 4.58-4.51 (m, 2H), 3.80-3.73 (m,2H), 3.33 (s, 3H). MS: 354 (MH⁺).

Example 61(R)-5-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)pyrrolidin-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 8.03-7.93 (m, 3H), 7.89-7.80 (m, 2H), 7.73(d, J=8.7 Hz, 1H), 7.50-7.43 (m, 2H), 4.44 (dd, J=10.3, 4.3 Hz, 1H),4.29 (dd, J=10.3, 6.5 Hz, 1H), 4.08-3.97 (m, 1H), 2.39-2.08 (m, 3H),1.96-1.84 (m, 1H). MS: 393 (MH⁺).

Example 62(S)-5-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)pyrrolidin-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 8.03-7.93 (m, 3H), 7.89-7.80 (m, 2H), 7.73(dd, J=8.8, 0.8 Hz, 1H), 7.51-7.43 (m, 2H), 4.44 (dd, J=10.3, 4.3 Hz,1H), 4.29 (dd, J=10.3, 6.6 Hz, 1H), 4.08-3.97 (m, 1H), 2.39-2.08 (m,3H), 1.96-1.84 (m, 1H). MS: 393 (MH⁺).

Example 633-(2-(4H-1,2,4-triazol-4-yl)ethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.66 (s, 2H), 8.09-8.04 (m, 1H), 7.96 (dd,J=8.8, 1.9 Hz, 1H), 7.89-7.81 (m, 2H), 7.72 (dd, J=8.8, 0.7 Hz, 1H),7.50-7.43 (m, 2H), 4.70 (t, J=4.8 Hz, 2H), 4.57 (t, J=4.8 Hz, 2H). MS:391 (MH⁺).

Example 643-((1-phenyl-1H-imidazol-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 7.96 (dd, J=8.8, 1.9 Hz, 1H), 7.93-7.88 (m,1H), 7.88-7.81 (m, 2H), 7.71 (dd, J=8.8, 0.8 Hz, 1H), 7.59-7.35 (m, 8H),7.16 (d, J=1.3 Hz, 1H), 5.42 (s, 2H). MS: 452 (MH⁺).

Example 653-((1-(pyridin-2-yl)-1H-pyrazol-4-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.86 (s, 1H), 8.47 (ddd, J=4.9, 1.8, 0.9 Hz,1H), 8.06-7.89 (m, 5H), 7.90-7.79 (m, 2H), 7.74 (d, J=8.8 Hz, 1H),7.47-7.39 (m, 2H), 7.37 (ddd, J=7.2, 4.9, 1.1 Hz, 1H), 5.50 (s, 2H). MS:453 (MH⁺).

Example 663-(2-(1H-imidazol-2-yl)ethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 11.85 (s, 1H), 7.99-7.89 (m, 2H), 7.90-7.80(m, 2H), 7.76-7.69 (m, 1H), 7.48-7.41 (m, 2H), 6.90 (s, 2H), 4.72 (t,J=6.7 Hz, 2H), 3.22 (t, J=6.6 Hz, 2H). MS: 390 (MH⁺).

Example 673-((4-methoxypyrimidin-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (d, J=5.8 Hz, 1H), 8.09-8.03 (m, 1H),7.98 (dd, J=8.8, 1.9 Hz, 1H), 7.92-7.83 (m, 2H), 7.73 (dd, J=8.7, 0.8Hz, 1H), 7.48-7.41 (m, 2H), 6.88 (d, J=5.8 Hz, 1H), 5.57 (s, 2H), 3.83(s, 3H). MS: 418 (MH⁺).

Example 683-(2-(1H-pyrazol-1-yl)propoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 7.94 (dd, J=8.8, 1.9 Hz, 1H), 7.91-7.85 (m,2H), 7.85-7.78 (m, 2H), 7.72 (d, J=8.8 Hz, 1H), 7.48-7.41 (m, 3H), 6.22(t, J=2.1 Hz, 1H), 5.01-4.88 (m, 1H), 4.74-4.61 (m, 2H), 1.55 (d, J=6.9Hz, 3H). MS: 404 (MH⁺).

Example 693-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (dd, J=8.8, 1.8 Hz, 1H), 7.90-7.78 (m,3H), 7.73 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.5, 1.3 Hz, 2H), 5.77 (s, 1H),4.71 (t, J=5.2 Hz, 2H), 4.43 (t, J=5.2 Hz, 2H), 2.23 (s, 3H), 2.04 (s,3H). MS: 418 (MO.

Example 703-((4-morpholinopyrimidin-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.19 (d, J=6.2 Hz, 1H), 8.04 (dd, J=1.9, 0.8Hz, 1H), 7.97 (dd, J=8.8, 1.9 Hz, 1H), 7.91-7.83 (m, 2H), 7.72 (dd,J=8.8, 0.7 Hz, 1H), 7.49-7.38 (m, 2H), 6.74 (d, J=6.2 Hz, 1H), 5.41 (s,2H), 3.59-3.47 (m, 8H). MS: 473 (MH⁺).

Example 71(S)-3-((1-methylpyrrolidin-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s, 1H), 8.12 (d, J=1.8 Hz, 1H), 7.99(dd, J=8.8, 1.9 Hz, 1H), 7.90-7.81 (m, 2H), 7.76 (d, J=8.9 Hz, 1H),7.51-7.43 (m, 2H), 4.86-4.71 (m, 2H), 3.95-3.77 (m, 1H), 3.73-3.55 (m,1H), 3.17-3.06 (m, 1H), 2.97 (s, 3H), 2.88-2.74 (m, 1H), 2.37-1.69 (m,3H). MS: 393 (MH⁺).

Example 72(R)-3-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)pyrrolidin-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (s, 1H), 7.99 (dt, J=4.8, 2.3 Hz, 2H),7.93-7.82 (m, 2H), 7.76 (d, J=9.2 Hz, 1H), 7.45 (dd, J=8.6, 1.2 Hz, 2H),5.40 (t, J=7.9 Hz, 1H), 3.39-3.20 (m, 2H), 2.78-2.66 (m, 1H), 2.26-2.11(m, 1H). MS: 379 (MH⁺).

Example 733-(((5-methylpyrazin-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (s, 1H), 8.58 (s, 1H), 8.09-8.03 (m,1H), 7.97 (dd, J=8.8, 1.9 Hz, 1H), 7.90-7.82 (m, 2H), 7.73 (d, J=8.8 Hz,1H), 7.47-7.39 (m, 2H), 5.58 (s, 2H), 2.51 (s, 3H). MS: 402 (MH⁺).

Example 743-(pyridazin-3-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 9.25 (dd, J=5.0, 1.5 Hz, 1H), 8.09 (d, J=1.8Hz, 1H), 7.99 (dt, J=8.5, 1.9 Hz, 2H), 7.91-7.82 (m, 2H), 7.83-7.72 (m,2H), 7.44 (d, J=8.3 Hz, 2H), 5.79 (s, 2H). MS: 388 (MH⁺).

Example 753-(2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)ethyl)oxazolidin-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 7.96 (dd, J=8.8, 1.9 Hz, 1H), 7.94-7.90 (m,1H), 7.89-7.80 (m, 2H), 7.74 (d, J=8.8 Hz, 1H), 7.46 (d, J=8.3 Hz, 2H),4.58 (t, J=5.1 Hz, 2H), 4.25 (dd, J=8.9, 7.0 Hz, 2H), 3.75-3.63 (m, 4H).MS: 409 (MH⁺).

Example 763-(2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)ethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (dd, J=8.8, 1.9 Hz, 1H), 7.86 (dd,J=1.8, 0.8 Hz, 1H), 7.85-7.78 (m, 2H), 7.73 (dd, J=8.8, 0.8 Hz, 1H),7.45 (dd, J=8.5, 1.1 Hz, 2H), 4.73 (t, J=5.0 Hz, 2H), 4.53 (t, J=5.0 Hz,2H), 2.37 (s, 3H), 2.13 (s, 3H). MS: 419 (MH⁺).

Example 773-(2-(1H-1,2,4-triazol-1-yl)propoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (s, 1H), 7.98 (s, 1H), 7.95 (dd, J=8.8,1.9 Hz, 1H), 7.89 (dd, J=1.9, 0.8 Hz, 1H), 7.86-7.78 (m, 2H), 7.72 (dd,J=8.8, 0.8 Hz, 1H), 7.48-7.41 (m, 2H), 5.15-5.02 (in, 1H), 4.78-4.61 (m,2H), 1.59 (d, J=6.9 Hz, 3H). MS: 405 (MH⁺).

Example 783-(2-morpholinoethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 7.99-7.92 (m, 2H), 7.90-7.81 (m, 2H), 7.72(d, J=9.3 Hz, 1H), 7.45 (d, J=8.3 Hz, 2H), 4.54 (t, J=5.5 Hz, 2H),3.59-3.52 (m, 4H), 2.81 (t, J=5.5 Hz, 2H), 2.53-2.48 (in, 4H). MS: 409(MH⁺).

Example 793-(2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)propoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (dd, J=8.8, 1.8 Hz, 1H), 7.86-7.78 (m,3H), 7.73 (d, J=8.8 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 5.00-4.87 (m, 1H),4.65 (dd, J=10.6, 4.3 Hz, 1H), 4.58 (dd, J=10.5, 9.1 Hz, 1H), 2.36 (s,3H), 2.14 (s, 3H), 1.47 (d, J=6.7 Hz, 3H). MS: 433 (MH⁺).

Example 801-(2-((7-fluoro-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)ethyl)pyrrolidin-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (dd, J=12.2, 1.5 Hz, 1H), 7.93-7.82 (m,2H), 7.79 (d, J=1.5 Hz, 1H), 7.46 (d, J=8.3 Hz, 2H), 4.55 (t, J=5.2 Hz,2H), 3.67 (t, J=5.2 Hz, 2H), 3.48 (t, J=7.0 Hz, 2H), 2.19 (t, J=8.0 Hz,2H), 1.90 (p, J=7.6 Hz, 2H). MS: 425 (MH⁺).

Example 813-((4-methoxypyridin-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (d, J=5.7 Hz, 1H), 8.12-8.06 (m, 1H),7.98 (dd, J=8.8, 1.8 Hz, 1H), 7.92-7.83 (m, 2H), 7.74 (d, J=8.8 Hz, 1H),7.44 (d, J=8.3 Hz, 2H), 7.23 (d, J=2.5 Hz, 1H), 6.98 (dd, J=5.8, 2.5 Hz,1H), 5.49 (s, 2H), 3.84 (s, 3H). MS: 417 (MH⁺).

Example 823-(isoquinolin-3-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 9.36 (s, 1H), 8.16 (d, J=8.1 Hz, 1H), 8.12(s, 1H), 8.09 (d, J=1.8 Hz, 1H), 8.02 (d, J=8.2 Hz, 1H), 7.98 (dd,J=8.8, 1.9 Hz, 1H), 7.91-7.84 (m, 2H), 7.81 (ddd, J=8.2, 6.9, 1.3 Hz,1H), 7.75 (d, J=8.8 Hz, 1H), 7.71 (ddd, J=8.0, 7.0, 1.1 Hz, 1H), 7.44(d, J=8.3 Hz, 2H), 5.71 (s, 2H). MS: 437 (MH⁺).

Example 833-((1H-1,2,3-triazol-4-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.18-7.94 (m, 3H), 7.92-7.81 (m, 2H), 7.76(s, 1H), 7.57 (d, J=8.7 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 5.31 (s, 2H).MS: 377 (MH⁺).

Example 843-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-7-fluoro-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.66 (s, 1H), 8.03-7.93 (m, 2H), 7.93-7.83(m, 2H), 7.81 (d, J=1.5 Hz, 1H), 7.46 (d, J 8.3 Hz, 2H), 4.79 (t, J 4.9Hz, 2H), 4.72 (t, J 4.9 Hz, 2H). MS: 409 (MH⁺).

Example 854-(2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)ethyl)thiomorpholine1,1-dioxide

¹H NMR (400 MHz, DMSO-d₆) δ 7.96 (d, J=7.9 Hz, 2H), 7.88-7.81 (m, 2H),7.73 (d, J=9.6 Hz, 1H), 7.45 (d, J=8.3 Hz, 2H), 4.54 (t, J=5.4 Hz, 2H),3.11-2.79 (m, 10H). S: 457 (MH⁺).

Example 865-(4-(trifluoromethoxy)phenyl)-3-((4-(trifluoromethyl)pyrimidin-2-yl)methoxy)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 9.22 (d, J=5.1 Hz, 1H), 8.10-8.04 (m, 1H),8.02 (d, J=5.1 Hz, 1H), 8.00-7.92 (m, 1H), 7.91-7.84 (m, 2H), 7.73 (d,J=8.8 Hz, 1H), 7.49-7.41 (m, 2H), 5.81 (s, 2H). MS: 456 (MH⁺).

Example 877-methyl-3-((1-methyl-11H-1,2,3-triazol-4-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.86-7.81 (m, 2H), 7.80 (dd,J=2.0, 1.1 Hz, 1H), 7.78-7.74 (m, 1H), 7.45-7.37 (m, 2H), 5.53 (s, 2H),4.06 (s, 3H), 2.51 (s, 3H). m/z: 405 (MH+)

Example 881-(2-((7-methyl-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)ethyl)pyrrolidin-2-one

1H NMR (400 MHz, DMSO-d6) δ 7.85-7.79 (m, 2H), 7.78 (d, J=1.7 Hz, 1H),7.71 (d, J=1.6 Hz, 1H), 7.43 (d, J=8.3 Hz, 2H), 4.51 (t, J=5.3 Hz, 2H),3.65 (t, J=5.3 Hz, 2H), 3.46 (t, J=7.0 Hz, 2H), 2.49 (s, 3H), 2.18 (t,J=8.1 Hz, 2H), 1.89 (p, J=7.6 Hz, 2H). m/z: 421 (MH+)

Example 893-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-7-methyl-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.98 (s, 1H), 7.84-7.80 (m,2H), 7.79 (t, J=1.5 Hz, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.44 (dt, J=8.2,1.2 Hz, 2H), 4.83-4.65 (m, 4H), 2.50 (s, 3H). m/z: 405 (MH+)

Example 903-((4-methoxypyrimidin-2-yl)methoxy)-7-methyl-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J=5.8 Hz, 1H), 7.90-7.83 (m, 3H),7.81 (dd, J=1.7, 1.0 Hz, 1H), 7.48-7.40 (m, 2H), 6.88 (d, J=5.8 Hz, 1H),5.56 (s, 2H), 3.84 (s, 3H), 2.50 (s, 3H). m/z: 432 (MH+)

Example 917-methyl-3-(oxazol-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J=0.9 Hz, 1H), 7.89-7.80 (m, 4H),7.47-7.39 (m, 2H), 7.32 (d, J=0.9 Hz, 1H), 5.61 (s, 2H), 2.51 (s, 3H).m/z: 391 (MH+)

Example 923-((3-methyloxetan-3-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-ol (100 mg, 0.34 mmol),3-bromomethyl-3-methyloxetane (150 mg, 0.91 mmol) and cesium carbonate(300 mg) were combined in 5 mL DMF and stirred at ambient temperatureuntil HPLC showed complete disappearance of benzisoxazole startingmaterial. The reaction mixture was diluted with 60 mL ethyl acetate,washed with water and brine and evaporated under vacuum. Flashchromatographic purification on 12 g silica gel with 0-60% ethyl acetatein hexane gave the title compound (80 mg, 0.21 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 8.02-7.93 (m, 2H), 7.91-7.82 (m, 2H), 7.73(dd, J=8.7, 0.8 Hz, 1H), 7.48-7.41 (m, 2H), 4.57 (d, J=5.9 Hz, 2H), 4.53(s, 2H), 4.33 (d, J=5.9 Hz, 2H), 1.42 (s, 3H). MS: 380 (MO.

The following compounds were synthesized using the same procedure butsubstituting the appropriate halide:

Example 933-((3-methylpyridin-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.44-8.37 (m, 1H), 8.03-7.93 (m, 2H),7.90-7.81 (m, 2H), 7.74 (dt, J=8.8, 0.7 Hz, 1H), 7.72-7.66 (m, 1H),7.46-7.38 (m, 2H), 7.34 (dd, J=7.7, 4.8 Hz, 1H), 5.59 (s, 2H), 2.42 (s,3H). MS: 401 (MH⁺).

Example 943-((3-fluoropyridin-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d₆) δ 8.47 (dt, J=4.7, 1.5 Hz, 1H), 8.03-7.94 (m,2H), 7.91-7.78 (m, 3H), 7.78-7.71 (m, 1H), 7.56 (dt, J=8.7, 4.5 Hz, 1H),7.48-7.38 (m, 2H), 5.64 (d, J=1.9 Hz, 2H). MS: 405 (MH⁺).

Example 953-((6-methylpyridin-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.07 (dd, J=1.9, 0.7 Hz, 1H), 7.97 (dd,J=8.8, 1.9 Hz, 1H), 7.91-7.83 (m, 2H), 7.79-7.68 (m, 2H), 7.49-7.40 (m,3H), 7.24 (d, J=7.7 Hz, 1H), 5.50 (s, 2H), 2.48 (s, 3H). MS: 401 (MH⁺).

Example 963-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (dd, J=1.9, 0.7 Hz, 1H), 8.00 (dd,J=8.8, 1.9 Hz, 1H), 7.92-7.83 (m, 2H), 7.77 (dd, J=8.8, 0.7 Hz, 1H),7.48-7.40 (m, 2H), 5.71 (s, 2H), 2.28 (tt, J=8.4, 4.9 Hz, 1H), 1.25-1.09(m, 2H), 1.08-0.97 (m, 2H). MS: 418 (MH⁺).

Example 97(3-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)oxetan-3-yl)methanol

¹H NMR (400 MHz, DMSO-d₆) δ 8.02-7.93 (m, 2H), 7.90-7.82 (m, 2H),7.77-7.70 (m, 1H), 7.45 (d, J=8.3 Hz, 2H), 5.06 (t, J=5.4 Hz, 1H), 4.61(s, 2H), 4.52 (d, J=6.0 Hz, 2H), 4.41 (d, J=6.0 Hz, 2H), 3.78 (d, J=5.4Hz, 2H). MS: 396 (MH⁺).

Example 983-(1-(pyridin-2-yl)ethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (ddd, J=4.9, 1.8, 0.9 Hz, 1H),8.08-8.02 (m, 1H), 7.96 (dd, J=8.8, 1.9 Hz, 1H), 7.91-7.85 (m, 2H), 7.81(td, J=7.7, 1.8 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.59 (dt, J=8.0, 1.1Hz, 1H), 7.49-7.38 (m, 2H), 7.33 (ddd, J=7.6, 4.8, 1.1 Hz, 1H), 5.96 (q,J=6.5 Hz, 1H), 1.75 (d, J=6.5 Hz, 3H). MS: 401 (MH⁺).

Example 993-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.06-8.02 (m, 1H), 8.00 (dd, J=8.8, 1.9 Hz,1H), 7.91-7.82 (m, 2H), 7.77 (d, J=8.8 Hz, 1H), 7.48-7.40 (m, 2H), 5.75(s, 2H), 2.53 (s, 3H). MS: 392 (MH⁺).

Example 1003-((5-isopropyl-1,3,4-oxadiazol-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.07-8.02 (m, 1H), 8.00 (dd, J=8.8, 1.4 Hz,1H), 7.91-7.82 (m, 2H), 7.77 (d, J=8.8 Hz, 1H), 7.48-7.40 (m, 2H), 5.75(s, 2H), 3.22 (hept, J=7.0 Hz, 1H), 1.30 (d, J=7.0, Hz, 6H). MS: 420(MH⁺).

Example 1013-((5-methyl-1,3,4-thiadiazol-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.04-7.96 (m, 2H), 7.91-7.82 (m, 2H), 7.77(dd, J=8.7, 0.9 Hz, 1H), 7.48-7.40 (m, 2H), 5.91 (s, 2H), 2.74 (s, 3H).MS: 408 (MH⁺).

Example 1023-((3-methylisoxazol-5-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.02 (d, J=1.8 Hz, 1H), 7.99 (dd, J=8.8, 1.9Hz, 1H), 7.91-7.82 (m, 2H), 7.76 (d, J=8.8 Hz, 1H), 7.43 (dd, J=8.5, 1.3Hz, 2H), 6.63 (s, 1H), 5.62 (s, 2H), 2.25 (s, 3H). MS: 391 (MH⁺).

Example 1032-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)acetonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 8.06 (d, J=1.7 Hz, 1H), 8.02 (dd, J=8.8, 1.9Hz, 1H), 7.92-7.83 (m, 2H), 7.80 (d, J=8.8 Hz, 1H), 7.49-7.42 (m, 2H),5.50 (s, 2H). MS: 335 (MH⁺).

Example 1043-(((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methoxy)-7-fluoro-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (dd, J=12.3, 1.5 Hz, 1H), 7.95-7.87 (m,3H), 7.45 (d, J=8.3 Hz, 2H), 5.73 (s, 2H), 2.28 (tt, J=8.7, 4.9 Hz, 1H),1.20-1.09 (m, 2H), 1.08-0.97 (m, 2H). MS: 436 (MH⁺).

Example 1053-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methoxy)-7-methyl-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 7.90-7.80 (m, 4H), 7.47-7.39 (m, 2H), 5.70(s, 2H), 2.51 (s, 3H), 2.34-2.21 (m, 1H), 1.19-1.11 (m, 2H), 1.04-0.98(m, 2H). m/z: 432 (MH+)

Example 1067-methyl-3-((6-methylpyridin-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 7.90-7.83 (m, 3H), 7.82 (d, J=1.5 Hz, 1H),7.74 (t, J=7.7 Hz, 1H), 7.48-7.40 (m, 3H), 7.24 (d, J=7.7 Hz, 1H), 5.49(s, 2H), 2.51 (s, 3H), 2.48 (s, 3H). m/z: 415 (MH+)

Example 107 tert-butyl(S)-2-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)pyrrolidine-1-carboxylate

Diisopropylazodicarboxylate 40% solution in toluene (0.27 mL, 0.51 mmol)was added under stirring to a solution of5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-ol (100 mg, 0.34 mmol),triphenylphosphine on resin (3 mmol/g) (330 mg, 1 mmol), and1-methylimidazol-4-yl methanol (60 mg, 0.51 mmol) in THF. The reactionmixture was stirred at ambient temperature overnight. Volatiles wereevaporated under vacuum and the residue was purified on 12 g silica gelwith 0-60% ethyl acetate in hexane and gave the title compound (104 mg,0.22 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 8.00-7.92 (m, 2H), 7.89-7.81 (m, 2H), 7.72(d, J=9.3 Hz, 1H), 7.45 (d, J=8.3 Hz, 2H), 4.51-4.40 (m, 2H), 4.20-4.11(m, 1H), 3.34-3.25 (m, 2H), 2.09-1.93 (m, 3H), 1.86-1.78 (m, 1H), 1.35(s, 9H). MS: 479 (MH⁺).

Example 108(S)-3-(pyrrolidin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

Example 107 (95 mg, 0.20 mmol) was dissolved in 2 mL 4N HCl solution in1,4 dioxane and stirred at ambient temperature for two hours.Diethylether ether was added and the formed precipitate was filtered,washed with diethylether and dried, giving the title compound (76 mg,0.18 mmol) as the HCl salt.

¹H NMR (400 MHz, DMSO-d₆) δ 9.69 (br, 1H), 9.35 (br, 1H), 8.06-8.02 (m,1H), 7.99 (dd, J=8.8, 1.9 Hz, 1H), 7.88-7.80 (m, 2H), 7.76 (dd, J=8.8,0.8 Hz, 1H), 7.48 (dd, J 8.1, 1.6 Hz, 2H), 4.71 (dd, J=11.2, 3.8 Hz,1H), 4.61 (dd, J=11.2, 7.8 Hz, 1H), 4.10-3.98 (m, 1H), 3.32-3.16 (m,2H), 2.21-1.75 (m, 4H). MS: 379 (MH⁺).

Example 109(S)-1-(2-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)pyrrolidin-1-yl)ethan-1-one

Example 108 (65 mg, 0.16 mmol) was dissolved in 2 mL anhydrous pyridine.Acetic anhydride (0.1 mL) was added and the mixture was stirred atambient temperature for one hour. Volatiles were evaporated under vacuumand the residue was purified on 12 g silica gel with 0-60% ethyl acetatein hexane and gave the title compound (54 mg, 0.13 mmol). ¹H NMR (400MHz, DMSO-d₆) δ 8.01-7.91 (m, 2H), 7.90-7.81 (m, 2H), 7.78-7.69 (m, 1H),7.46 (d, J=8.5 Hz, 2H), 4.54-4.30 (m, 3H), 3.59-3.38 (m, 2H), 2.14-1.83(m, 7H). MS: 421 (MH⁺).

The following compounds were synthesized using the same route:

Example 1101-(3-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)azetidin-1-yl)ethan-1-one

¹H NMR (400 MHz, DMSO-d₆) δ 8.01-7.93 (m, 2H), 7.90-7.81 (m, 2H),7.77-7.70 (m, 1H), 7.49-7.41 (m, 2H), 4.60 (d, J=6.8 Hz, 2H), 4.25 (t,J=8.5 Hz, 1H), 4.06-3.92 (m, 2H), 3.72 (dd, J=9.6, 5.5 Hz, 1H),3.19-3.07 (m, 1H), 1.74 (s, 3H). MS: 407 (MH⁺).

Example 111 tert-butyl(S)-3-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)morpholine-4-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ 8.02-7.86 (m, 2H), 7.84-7.77 (m, 2H), 7.73(d, J=8.8 Hz, 1H), 7.44 (d, J=8.3 Hz, 2H), 4.76-4.33 (m, 3H), 3.98-2.96(m, 6H), 1.20 (s, 9H). MS: 495 (MH⁺).

Example 112 tert-butyl(R)-3-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)morpholine-4-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ 8.00-7.88 (m, 2H), 7.84-7.77 (m, 2H), 7.74(d, J=8.8 Hz, 1H), 7.45 (d, J=8.3 Hz, 2H), 4.75-4.32 (m, 3H), 3.97-3.02(m, 6H), 1.20 (s, 9H). MS: 495 (MH⁺).

Example 113(S)-3-(morpholin-3-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 9.86 (br, 2H), 8.20 (d, J=1.8 Hz, 1H), 7.99(dd, J=8.8, 1.9 Hz, 1H), 7.89-7.80 (m, 2H), 7.75 (d, J=8.9 Hz, 1H), 7.48(d, J=8.3 Hz, 2H), 4.72-4.57 (m, 2H), 4.09 (dd, J=12.1, 3.0 Hz, 1H),3.93 (dt, J=12.4, 3.1 Hz, 1H), 3.87: −3.70 (m, 3H), 3.46-3.26 (m, 1H),3.22-3.11 (m, 1H). MS: 395 (MH⁺).

Example 114(R)-3-(morpholin-3-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

¹H NMR (400 MHz, DMSO-d₆) δ 9.79 (s, 2H), 8.18 (d, J=1.8 Hz, 1H), 8.00(dd, J=8.8, 1.9 Hz, 1H), 7.89-7.80 (m, 2H), 7.76 (d, J=8.8 Hz, 1H), 7.48(d, J=8.3 Hz, 2H), 4.71-4.56 (m, 2H), 4.09 (dd, J=12.2, 3.1 Hz, 1H),3.98-3.70 (m, 4H), 3.41-3.27 (m, 1H), 3.23-3.11 (m, 1H). MS: 395 (MH⁺).

Example 115(S)-1-(3-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)morpholino)ethan-1-one

Mixture of amide isomers in NMR. ¹H NMR (400 MHz, DMSO-d₆) δ 8.00-7.79(m, 4H), 7.78-7.69 (m, 1H), 7.49-7.42 (m, 2H), 4.85-4.26 (m, 3H),4.15-3.75 (m, 3H), 3.64-2.85 (m, 3H), [2.10 (s), 1.98 (s) 3H]. MS: 437(MH⁺).

Example 116(R)-1-(3-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)methyl)morpholino)ethan-1-one

Mixture of amide isomers in NMR. ¹H NMR (400 MHz, DMSO-d₆) δ 8.00-7.79(m, 4H), 7.78-7.69 (m, 1H), 7.49-7.42 (m, 2H), 4.85-4.27 (m, 3H),4.15-3.77 (m, 3H), 3.64-2.84 (m, 3H), [2.10 (s), 1.98 (s) 3H]. MS: 437(MH⁺).

Example 117(R)-1-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)propan-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (br, 3H), 8.11 (d, J=1.8 Hz, 1H), 7.99(dd, J=8.9, 1.9 Hz, 1H), 7.87-7.78 (m, 2H), 7.75 (d, J=8.8 Hz, 1H),7.51-7.44 (m, 2H), 4.57 (dd, J=10.8, 3.8 Hz, 1H), 4.43 (dd, J=10.8, 7.0Hz, 1H), 3.79-3.72 (m, 1H), 1.33 (d, 0.1=6.6 Hz, 3H). MS: 353 (MH⁺).

Example 118(S)-3-methyl-1-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)butan-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (br, 3H), 8.16-8.10 (m, 1H), 7.99 (dd,J=8.8, 1.9 Hz, 1H), 7.87-7.79 (m, 2H), 7.76 (d, J=8.8 Hz, 1H), 7.49 (d,J=8.3 Hz, 2H), 4.66 (dd, J=11.2, 3.4 Hz, 1H), 4.53 (dd, J=11.2, 6.7 Hz,1H), 3.51-3.42 (m, 1H), 2.14 (h, J 6.9 Hz, 1H), 1.05 (d, J=6.8 Hz, 3H),1.02 (d, J=6.8 Hz, 3H). MS: 381 (MH⁺).

Example 119(R)-1-(1-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)propan-2-yl)pyrrolidin-2-one

Example 117 (23 mg, 0.059 mmol) was dissolved in 2 mL THF. Triethylamine(0.041 mL, 0.29 mmol) and then 4-chlorobutyryl chloride (11 mg, 0.077mmol) was added. The mixture was stirred at ambient temperature for 1hour and then diluted with EtOAc washed with water and brine,evaporated. The residue was dissolved in 5 mL THF. NaH 60% in oil (50mg) was added and the reaction mixture was stirred at ambienttemperature overnight. The reaction was quenched with 5 mL water,diluted with ethyl acetate, washed with water and brine, evaporated andpurified on 12 g silica gel with 0-100% ethyl acetate in hexane to yieldthe title compound (25 mg, 0.048 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (dd, J=8.8, 1.8 Hz, 1H), 7.91 (d, J=1.7Hz, 1H), 7.89-7.80 (m, 2H), 7.73 (d, J=8.8 Hz, 1H), 7.45 (d, J=8.4 Hz,2H), 4.56-4.39 (m, 3H), 3.46-3.34 (m, 2H), 2.22-2.13 (m, 2H), 1.94-1.77(m, 2H), 1.21 (d, J=6.4 Hz, 3H). MS: 421 (MH⁺).

The following compound was synthesized using the same procedure:

Example 120(S)-1-(3-methyl-1-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)butan-2-yl)pyrrolidin-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (dd, J=8.8, 1.9 Hz, 1H), 7.91-7.86 (m,1H), 7.86-7.79 (m, 2H), 7.73 (d, J=8.8 Hz, 1H), 7.49-7.42 (m, 2H),4.65-4.52 (m, 2H), 4.05 (ddd, J=10.4, 7.3, 4.3 Hz, 1H), 3.45-3.31 (m,2H), 2.28-2.12 (m, 2H), 2.11-1.97 (m, 1H), 1.96-1.81 (m, 2H), 0.99 (d,J=6.6 Hz, 3H), 0.82 (d, J=6.7 Hz, 3H). MS: 449 (MH⁺).

Example 1211-(pyrrolidin-1-yl)-2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)ethan-1-one

Step 1: 5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-ol (500 mg,1.69 mmol), tert-butyl 2-bromoacetate (500 mg, 2.56 mmol) and cesiumcarbonate (1.65 g) were combined in 5 mL DMF and stirred at ambienttemperature for 1 hour. The reaction mixture was diluted with 80 mLethyl acetate, washed with water and brine and evaporated under vacuum.Flash chromatographic purification on 12 g silica gel with 0-100% ethylacetate in hexane gave tert-butyl2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)acetate (285mg, 0.70 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 8.04-8.01 (m, 1H), 7.98 (dd, J=8.8, 1.8 Hz,1H), 7.90-7.83 (m, 2H), 7.75 (d, J=8.8 Hz, 1H), 7.45 (d, J=8.0 Hz, 2H),5.00 (s, 2H), 1.42 (s, 9H). MS: 410 (MH⁺).

Step 2: tert-Butyl2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)acetate (285mg, 0.70 mmol) was dissolved in 5 mL dichloromethane. 2 mLtrifluoroacetic acid was added and the mixture was stirred at ambienttemperature for 3 hours. Volatiles were evaporated under vacuum and theresidue was crystallized from ethyl acetate/hexane to give2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)acetic acid(160 mg, 0.453 mmol).

Step 3:2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)acetic acid(50 mg, 0.142 mmol) was dissolved in 3 mL DMF. Pyrrolidine (30 mg, 0.425mmol) was added followed by addition of HATU (81 mg, 0.212 mmol). Themixture was stirred at ambient temperature overnight, then diluted with60 mL ethyl acetate, washed with water and brine, and evaporated. Theproduct was purified on 12 g silica gel with 0-100% ethyl acetate inhexane followed by recrystallization from acetonitrile/water to give thetitle compound (30 mg, 0.073 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 8.05-8.00 (m, 1H), 7.97 (dd, J=8.8, 1.9 Hz,1H), 7.91-7.83 (m, 2H), 7.74 (d, J=8.8 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H),5.12 (s, 2H), 3.45 (t, J=6.8 Hz, 2H), 3.33 (t, J=6.9 Hz, 2H), 1.91 (p,J=6.8 Hz, 2H), 1.78 (p, J=6.9 Hz, 2H). MS: 407 (MH⁺).

The following compound was synthesized using the same procedure:

Example 122N-isopropyl-2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)acetamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.09-8.02 (m, 2H), 7.97 (dd, J=8.8, 1.9 Hz,1H), 7.90-7.81 (m, 2H), 7.73 (d, J=8.8 Hz, 1H), 7.50-7.43 (m, 2H), 4.83(s, 2H), 3.99-3.86 (m, 1H), 1.08 (d, J=6.6 Hz, 6H). MS: 395 (MH⁺).

Example 123N-(2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)ethyl)pyrimidin-2-amine

2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)ethanaminehydrochloride (57 mg, 0.152 mmol) and 2-(methylsulfonyl)pyrimidine (96mg, 0.608 mmol) were dissolved in 2 mL ethanol in a microwave vial.Triethylamine (0.1 mL) was added and the mixture was heated at 120° C.for one hour in the microwave. All volatiles were removed under vacuumand the residue was purified on 12 g silica gel with 0-100% ethylacetate in hexane to give the title compound (40 mg, 0.096 mmol). MS:417 (MH⁺).

Example 1243-(pyrimidin-2-yloxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

Compound A (0.100 g, 0.34 mmol) and B (0.268 g, 1.69 mmol) were added toa 0.2-5 mL microwave tube. DMF (3 mL) was added. The mixture was stirredand microwaved at 120° C. for 30 min, and then filtered. The filtratewas purified by HPLC. The fractions from HPLC were combined, K₂CO₃ (0.5g) were added, extracted with EtOAc. The organic solution wasconcentrated. The resultant material was filtered through a short silicagel column with 1% MeOH in EtOAc to afford the title compound (6.4 mg,5%). 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J=4.8 Hz, 2H), 8.03 (dd,J=9.0, 1.8 Hz, 1H), 7.95-7.88 (in, 2H), 7.83-7.75 (m, 2H), 7.45 (t,J=4.8 Hz, 1H), 7.44-7.39 (m, 2H). m/z: 374 (MH+)

Example 1253-(pyridin-2-yloxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

Compound A (0.133 g, 0.45 mmol) and B (0.05 g, 0.45 mmol) were mixed andheated at 200° C. overnight. The mixture was purified by HPLC, thefractions were combined, K₂CO₃ (0.5 g) was added, extracted with EtOAc,concentrated, and then purified by preparative TLC (Rf=0.14 in 20%DCM/Hexane) to afford the title compound (4.3 mg, 3%).

1H NMR (400 MHz, DMSO-d6) δ 8.68-8.61 (m, 1H), 8.26 (dd, J=1.5, 0.8 Hz,1H), 8.12-8.03 (m, 2H), 7.80-7.71 (m, 2H), 7.59-7.51 (m, 2H), 7.50-7.41(m, 3H). m/z: 373 (MH⁺).

Example 126N-(pyrimidin-2-ylmethyl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-amine

A (3.13 g, 13.5 mmol), B (2.77 g, 13.5 mmol), Pd(dppf)Cl₂ (1.00 g, 1.35mmol), potassium carbonate (5.58 g, 40.4 mmol) were mixed. Toluene (30mL), 2-isopropanol (15 mL), water (20 mL) were added. The resultantmixture was stirred under the N₂ protection at 120° C. for 15 min, thereaction was complete. The resultant mixture was diluted with EtOAc,washed with brine, dried with MgSO₄, concentrated and purified withsilica gel column (R_(f)=0.16 with 2% EtOAc in Hexane) to afford thetarget product C (2.44 g, 58%).

C (0.050 g, 0.159 mmol), D (0.25 g, 2.0 mmol) and DBU (0.12 g) wereadded in a 0.2-0.5 ml microwave tube. The mixture was microwaved at 160C for 1.5 h. Water was added with stirring until precipitates wereformed, filtered, washed with water. The resultant precipitates werepurified by preparative TLC with 0.5% MeOH in EtOAc, then by HPLC. Thefractions from HPLC were combined, K₂CO₃ (0.5 g) were added, extractedwith EtOAc. The organic solution from the extraction was concentrated.The resultant material was filtrated through a short silica gel columnwith 1% MeOH in EtOAc to afford the title compound (5.8 mg, 9.4%).

1H NMR (400 MHz, DMSO-d6) δ 8.78 (dd, J=4.9, 0.9 Hz, 2H), 8.36-8.31 (m,1H), 7.89-7.83 (m, 1H), 7.83-7.76 (m, 2H), 7.70 (t, J=6.2 Hz, 1H), 7.54(d, J=8.7 Hz, 1H), 7.52-7.45 (m, 2H), 7.40 (t, J=4.9 Hz, 1H), 4.68 (d,J=6.1 Hz, 2H). m/z: 387 (MH+)

The following compounds were synthesized using the same procedure:

Example 1273-((4-methylpiperazin-1-yl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.25-8.08 (m, 1H), 7.92-7.79 (m, 3H), 7.66(d, J=8.7 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 3.54-3.45 (m, 4H), 2.53-2.47(m, 4H), 2.23 (s, 3H). m/z: 378 (MH+)

Example 128N-(cyclopropylmethyl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-amine

1H NMR (400 MHz, DMSO-d6) δ 8.04-7.94 (m, 1H), 7.58 (dd, J=8.7, 1.9 Hz,1H), 7.56-7.49 (m, 2H), 7.27 (d, J=8.7 Hz, 1H), 7.25-7.18 (m, 2H), 6.82(t, J=5.5 Hz, 1H), 2.86 (t, J=6.2 Hz, 2H), 1.01-0.82 (m, 1H), 0.32-0.19(m, 2H), 0.08-0.01 (m, 2H). m/z: 349 (MH+)

Example 129N-((6-methylpyridin-2-yl)methyl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-amine

1H NMR (400 MHz, DMSO-d6) δ 8.27 (dd, J=1.9, 0.8 Hz, 1H), 7.85 (dd,J=8.7, 1.9 Hz, 1H), 7.81-7.75 (m, 2H), 7.71-7.59 (m, 2H), 7.55 (dd,J=8.7, 0.7 Hz, 1H), 7.52-7.43 (m, 2H), 7.23 (d, J=7.8 Hz, 1H), 7.13 (d,J=7.6 Hz, 1H), 4.51 (d, J=6.0 Hz, 2H), 2.46 (s, 3H). m/z: 400 (MH+)

Example 130 3-morpholino-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.23-8.17 (m, 1H), 7.91-7.80 (m, 3H), 7.68(d, J=8.8 Hz, 1H), 7.51-7.40 (m, 2H), 3.85-3.72 (m, 4H), 3.57-3.43 (m,4H). m/z: 365 (MH⁺).

Example 131N-isopropyl-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-amine

1H NMR (400 MHz, DMSO-d6) δ 8.21 (dd, J=1.9, 0.8 Hz, 1H), 7.83 (dd,J=8.7, 1.9 Hz, 1H), 7.80-7.75 (m, 2H), 7.52 (dd, J=8.7, 0.8 Hz, 1H),7.50-7.44 (m, 2H), 6.80 (d, 3=7.1 Hz, 1H), 3.86-3.62 (m, 1H), 1.25 (d,J=6.4 Hz, 6H). m/z: 337 (MH⁺).

Example 1323-(1H-imidazol-1-yl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.73 (t, J=1.1 Hz, 1H), 8.41 (dd, J=1.7, 0.8Hz, 1H), 8.11 (dd, J=8.9, 1.8 Hz, 1H), 8.08 (t, J=1.4 Hz, 1H), 8.01-7.93(m, 3H), 7.54-7.46 (m, 2H), 7.30 (dd, J=1.5, 0.8 Hz, 1H). m/z: 346(MH⁺).

Example 133N,N-dimethyl-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-amine

1H NMR (400 MHz, DMSO-d6) δ 8.14 (dd, J=1.8, 0.8 Hz, 1H), 7.89-7.80 (m,3H), 7.62 (dd, J=8.7, 0.8 Hz, 1H), 7.49-7.40 (m, 2H), 3.16 (s, 6H). m/z:323 (MH⁺).

Example 134(R)-5-(((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)amino)methyl)pyrrolidin-2-one

1H NMR (400 MHz, DMSO-d6) δ 8.21-8.14 (m, 1H), 7.85 (dd, J=8.7, 1.9 Hz,1H), 7.81-7.74 (m, 2H), 7.71 (s, 1H), 7.55 (d, J=8.7 Hz, 1H), 7.52-7.44(m, 2H), 7.07 (t, J=5.9 Hz, 1H), 3.86 (p, J=6.0 Hz, 1H), 3.40-3.21 (m,2H), 2.28-2.03 (m, 3H), 1.89-1.72 (m, 1H). m/z: 392 (MH⁺).

Example 1351-(2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)amino)ethyl)pyrrolidin-2-one

1H NMR (400 MHz, DMSO-d6) δ 8.12 (dd, J=1.9, 0.8 Hz, 1H), 7.84 (dd,J=8.7, 1.9 Hz, 1H), 7.79-7.72 (m, 2H), 7.55 (d, J=8.7 Hz, 1H), 7.51-7.45(m, 2H), 7.11 (t, J=5.6 Hz, 1H), 3.51-3.35 (m, 6H), 2.17 (t, J=8.1 Hz,2H), 1.89 (tt, J=7.8, 6.6 Hz, 2H). m/z: 406 (MH⁺).

Example 1363-(1H-1,2,4-triazol-1-yl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.57 (s, 1H), 8.42 (dd, J=1.8,0.8 Hz, 1H), 8.13 (dd, J=8.9, 1.9 Hz, 1H), 8.01 (dd, J=8.9, 0.8 Hz, 1H),7.92-7.84 (m, 2H), 7.55-7.45 (m, 2H). m/z: 347 (MH⁺).

Example 137N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-amine

1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.10 (dd, J=1.9, 0.8 Hz, 1H),7.98 (s, 1H), 7.85 (dd, J=8.7, 1.9 Hz, 1H), 7.79-7.71 (m, 2H), 7.57 (d,J=8.7 Hz, 1H), 7.51-7.43 (m, 2H), 7.22 (t, J=5.8 Hz, 1H), 4.47 (t, J=5.8Hz, 2H), 3.70 (q, J=5.9 Hz, 2H). m/z: 390 (MH⁺).

Example 1383-(2-methyl-1H-imidazol-1-yl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.15-8.08 (m, 2H), 8.03-7.97 (m, 1H), 7.95(d, J=1.6 Hz, 1H), 7.94-7.89 (m, 2H), 7.51-7.44 (m, 2H), 7.13 (d, J=1.6Hz, 1H), 2.53 (s, 3H). m/z: 360 (MH⁺).

Example 1393-((4-methyl-1H-imidazol-1-yl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J=1.4 Hz, 1H), 8.43-8.38 (m, 1H),8.09 (dd, J=8.9, 1.7 Hz, 1H), 7.99-7.92 (m, 3H), 7.77 (t, J=1.3 Hz, 1H),7.53-7.47 (m, 2H), 2.23 (d, J=1.1 Hz, 3H). m/z: 360 (MH⁺).

Example 1403-((4-chloro-1H-imidazol-1-yl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J=1.6 Hz, 1H), 8.43 (dd, J=1.7, 0.8Hz, 1H), 8.25 (d, J=1.6 Hz, 1H), 8.12 (dd, J=8.9, 1.7 Hz, 1H), 8.02-7.94(m, 3H), 7.54-7.45 (m, 2H). m/z: 380 (MH⁺).

Example 1413-((3-methyl-1H-1,2,4-triazol-1-yl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.40 (dd, J=1.9, 0.8 Hz, 1H),8.10 (dd, J=8.9, 1.8 Hz, 1H), 7.99 (d, J=8.9, 1H), 7.89-7.85 (m, 2H),7.56-7.44 (m, 2H), 2.47 (s, 3H). m/z: 361 (MH⁺).

Example 1423-((4-phenyl-1H-imidazol-1-yl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J=1.3 Hz, 1H), 8.55 (d, J=1.3 Hz,1H), 8.51 (dd, J=1.8, 0.8 Hz, 1H), 8.12 (dd, J=8.9, 1.7 Hz, 1H),8.03-7.94 (m, 5H), 7.56-7.48 (m, 2H), 7.43 (dd, J=8.4, 7.1 Hz, 2H),7.34-7.25 (m, 1H). m/z: 422 (MH⁺).

Example 1433-((4-(tert-butyl)-1H-imidazol-1-yl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J=1.3 Hz, 1H), 8.43-8.39 (m, 1H),8.08 (dd, J=8.9, 1.7 Hz, 1H), 8.00-7.92 (m, 3H), 7.61 (d, J=1.4 Hz, 1H),7.52-7.46 (m, 2H), 1.30 (s, 9H). m/z: 402 (MH⁺).

Example 1443-(2-isopropyl-1H-imidazol-1-yl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.11 (dd, J=8.8, 1.8 Hz, 1H), 8.05 (dd,J=1.8, 0.8 Hz, 1H), 8.01 (dd, J=8.8, 0.8 Hz, 1H), 7.94-7.89 (m, 2H),7.87 (d, J=1.5 Hz, 1H), 7.51-7.44 (m, 2H), 7.15 (d, J=1.5 Hz, 1H), 3.37(p, J=6.8 Hz, 1H), 1.23 (d, J=6.8 Hz, 6H). m/z: 388 (MH⁺).

Example 1455-(4-(trifluoromethoxy)phenyl)-3-((4-(trifluoromethyl)-1H-imidazol-1-yl)benzo[d]isoxazole

1H NMR (400 MHz, DMSO-d6) δ 8.87 (dd, J=1.4, 0.8 Hz, 1H), 8.79-8.74 (m,1H), 8.45 (dd, J=1.7, 0.8 Hz, 1H), 8.13 (dd, J=8.9, 1.7 Hz, 1H), 8.01(dd, J=8.9, 0.8 Hz, 1H), 7.99-7.93 (m, 2H), 7.55-7.47 (m, 2H). m/z: 414(MH⁺).

Example 146(1-(5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)-1H-imidazol-4-yl)methanol

1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J=1.4 Hz, 1H), 8.40 (dd, J=1.7, 0.8Hz, 1H), 8.10 (dd, J=8.9, 1.7 Hz, 1H), 8.01-7.93 (m, 3H), 7.84 (q, J=1.0Hz, 1H), 7.53-7.45 (m, 2H), 5.10 (t, J=5.7 Hz, 1H), 4.48 (dd, J=5.7, 1.0Hz, 2H). m/z: 376 (MH⁺).

Example 147 5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-amine

A (0.575 g, 2.70 mmol), B (0.834 g, 4.05 mmol), Pd(dppf)Cl₂ (0.200 g,0.27 mmol), Potassium carbonate (0.746 g, 5.40 mmol) were mixed. Toluene(4 mL), 2-isopropanol (2 mL), water (4 mL) were added. The vial was thencapped tight, stirred at 100° C. for 3.6 h. The mixture was diluted withEtOAc, washed with brine, dried with MgSO₄, concentrated and purified bysilica gel column (Rf=0.13 in 20% EtOAc/hexane) to afford the titlecompound (0.523 g, 66%).

1H NMR (400 MHz, DMSO-d6) δ 8.17-8.12 (m, 1H), 7.83 (dd, J=8.7, 1.9 Hz,1H), 7.80-7.74 (m, 2H), 7.56-7.50 (m, 1H), 7.50-7.44 (m, 2H), 6.45 (s,2H). m/z: 295 (MH⁺).

Example 1483-(pyrimidin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)isoxazolo[5,4-c]pyridine

Example 148 was prepared using a similar synthetic procedure as Example1 using the appropriate starting materials.

¹H NMR (400 MHz, DMSO-d₆) δ 9.19 (d, J=1.1 Hz, 1H), 8.84 (d, J=4.9 Hz,2H), 8.48 (d, J=1.2 Hz, 1H), 8.35-8.26 (m, 2H), 7.53-7.43 (m, 3H), 5.73(s, 2H). MS: 389 (MH⁺).

Example 149N-((4-methoxypyrimidin-2-yl)methyl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-amine

Example 147 (0.1 g, 0.34 mmol), C (0.047 g, 0.34 mmol) were mixed inMeOH (2 mL), two drops of HOAc was added. The suspension was stirred atroom temperature for 2-3 days. Sodium cyanoborohydride (0.180 g, 2.35mmol) was added. The resultant mixture was stirred at room temperatureovernight, quenched with aqueous NaHCO₃, extracted with EtOAc, washedwith brine, concentrated, and purified with HPLC. The resultant productin TFA salt form was desalted with K₂CO₃/EtOAc extraction to affordparent compound the title compound (0.0357 g, 25%).

1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J=5.8 Hz, 1H), 8.35-8.31 (m, 1H),7.85 (dd, J=8.7, 1.9 Hz, 1H), 7.83-7.75 (m, 2H), 7.59 (t, J=6.2 Hz, 1H),7.54 (d, J=8.7 Hz, 1H), 7.52-7.45 (m, 2H), 6.82 (d, J=5.8 Hz, 1H), 4.58(d, J=6.2 Hz, 2H), 3.87 (s, 3H). m/z: 417 (MH+).

Example 150N,N-diethyl-2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)acetamide

Example 150 was prepared using a similar synthetic procedure as Example121 using the appropriate starting materials.

¹H NMR (400 MHz, DMSO-d₆) δ 8.03-7.93 (m, 2H), 7.90-7.82 (m, 2H), 7.73(d, J=8.7 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 5.21 (s, 2H), 3.36-3.29 (m,4H), 1.17 (t, J=7.1 Hz, 3H), 1.03 (t, J=7.0 Hz, 3H). MS: 409 (MH⁺).

Example 1513-(pyrazin-2-ylmethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

Example 151 was prepared using a similar synthetic procedure as Example43 using the appropriate starting materials.

¹H NMR (400 MHz, DMSO-d₆) δ 8.97 (d, J=1.4 Hz, 1H), 8.73-8.65 (m, 2H),8.11 (d, J=1.8 Hz, 1H), 7.99 (dd, J=8.9, 1.9 Hz, 1H), 7.92-7.83 (m, 2H),7.75 (d, J=8.8 Hz, 1H), 7.48-7.41 (m, 2H), 5.65 (s, 2H). MS: 388 (MH⁺).

Example 1523-((3-methylpyrazin-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

Example 152 was prepared using a similar synthetic procedure as Example43 using the appropriate starting materials.

¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (d, J=2.5 Hz, 1H), 8.48 (d, J=2.6 Hz,1H), 8.02 (d, J=1.9 Hz, 1H), 7.97 (dd, J=9.0, 1.9 Hz, 1H), 7.86 (d,J=8.5 Hz, 2H), 7.74 (d, J=8.8 Hz, 1H), 7.43 (d, J=8.2 Hz, 2H), 5.67 (s,2H), 2.64 (s, 3H). MS: 402 (MH⁺).

Example 1533-(1-(5-methyl-1,3,4-oxadiazol-2-yl)ethoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

Example 153 was prepared using a similar synthetic procedure as Example43 using the appropriate starting materials.

¹H NMR (400 MHz, DMSO-d₆) δ 8.03-7.95 (m, 2H), 7.92-7.83 (m, 2H), 7.76(d, J=8.6 Hz, 1H), 7.44 (d, J=8.3 Hz, 2H), 6.25 (q, J=6.6 Hz, 1H), 2.51(s, 3H), 1.85 (d, J=6.6 Hz, 3H). MS: 406 (MH⁺).

Example 1543-((5-cyclopropyl-1,3,4-thiadiazol-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

Example 154 was prepared using a similar synthetic procedure as Example92 using the appropriate starting materials.

¹H NMR (400 MHz, DMSO-d₆) δ 8.04-7.95 (m, 2H), 7.90-7.82 (m, 2H), 7.77(d, J=8.7 Hz, 1H), 7.44 (d, J=7.8 Hz, 2H), 5.88 (s, 2H), 2.55 (tt,J=8.3, 4.8 Hz, 1H), 1.28-1.15 (m, 2H), 1.07-0.98 (m, 2H). MS: 434 (MH⁺).

Example 1557-fluoro-3-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazole

Example 155 was prepared using a similar synthetic procedure as Example92 using the appropriate starting materials.

¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (dd, J=12.3, 1.5 Hz, 1H), 7.95-7.87 (m,3H), 7.48-7.41 (m, 2H), 5.78 (s, 2H), 2.54 (s, 3H). MS: 410 (MH⁺).

Example 156N-(oxazol-2-ylmethyl)-5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-amine

Example 156 was prepared using a similar synthetic procedure as Example149 using the appropriate starting materials.

¹H NMR (400 MHz, DMSO-d₆) δ 8.22 (dd, J=1.9, 0.8 Hz, 1H), 8.06 (d, J=0.9Hz, 1H), 7.86 (dd, J=8.8, 1.9 Hz, 1H), 7.82-7.73 (m, 3H), 7.57 (d, J=8.7Hz, 1H), 7.52-7.44 (m, 2H), 7.17 (d, J=0.9 Hz, 1H), 4.61 (d, J=6.0 Hz,2H). m/z: 376 (MH⁺).

Example 157 tert-butyl2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)acetate

5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-ol (500 mg, 1.69 mmol),tert-butyl 2-bromoacetate (500 mg, 2.56 mmol) and cesium carbonate (1.65g) were combined in 5 mL DMF and stirred at ambient temperature for 1hour. The reaction mixture was diluted with 80 mL ethyl acetate, washedwith water and brine and evaporated under vacuum. Flash chromatographicpurification on 12 g silica gel with 0-100% ethyl acetate in hexane gavetert-butyl2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)acetate (285mg, 0.70 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 8.04-8.01 (m, 1H), 7.98 (dd, J=8.8, 1.8 Hz,1H), 7.90-7.83 (m, 2H), 7.75 (d, J=8.8 Hz, 1H), 7.45 (d, J=8.0 Hz, 2H),5.00 (s, 2H), 1.42 (s, 9H). MS: 410 (MH⁺).

Example 158

Hard gelatin capsules containing the following ingredients are prepared:

Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules.

Example 159

A tablet Formula Is prepared using the ingredients below:

Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The components are blended and compressed to form tablets.

Example 160

A dry powder inhaler formulation is prepared containing the followingcomponents:

Ingredient Weight % Active Ingredient 5 Lactose 95

The active ingredient is mixed with the lactose and the mixture is addedto a dry powder inhaling appliance.

Example 161

Tablets, each containing 30 mg of active ingredient, are prepared asfollows:

Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg  Starch 45.0mg  Microcrystalline cellulose 35.0 mg  Polyvinylpyrrolidone 4.0 mg (as10% solution in sterile water) Sodium carboxymethyl starch 4.5 mgMagnesium stearate 0.5 mg Talc 1.0 mg Total 120 mg 

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50° C. to 60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

Example 162

Suppositories, each containing 25 mg of active ingredient are made asfollows:

Ingredient Amount Active Ingredient   25 mg Saturated fatty acidglycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

Example 163

Suspensions, each containing 50 mg of active ingredient per 5.0 mL doseare made as follows:

Ingredient Amount Active Ingredient 50.0 mg Xanthan gum  4.0 mg Sodiumcarboxymethyl cellulose (11%) 50.0 mg Microcrystalline cellulose (89%)Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purifiedwater to  5.0 mL

The active ingredient, sucrose and xanthan gum are blended, passedthrough a No. 10 mesh U.S. sieve and then mixed with a previously madesolution of the microcrystalline cellulose and sodium carboxymethylcellulose in water. The sodium benzoate, flavor and color are dilutedwith some of the water and added with stirring. Sufficient water is thenadded to produce the required volume.

Example 164

A subcutaneous formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 5.0 mg Corn Oil 1.0 mL

Example 165

An injectable preparation is prepared having the following composition:

Ingredients Amount Active ingredient 2.0 mg/mL Mannitol, USP  50 mg/mLGluconic acid, USP q.s. (pH 5-6) water (distilled, sterile) q.s. to 1.0mL Nitrogen Gas, NF q.s.

Example 166

A topical preparation is prepared having the following composition:

Ingredients grams Active ingredient 0.2-10 Span 60 2.0 Tween 60 2.0Mineral oil 5.0 Petrolatum 0.10 Methyl paraben 0.15 Propyl paraben 0.05BHA (butylated hydroxy anisole) 0.01 Water q.s. to 100

All of the above ingredients, except water, are combined and heated to60° C. with stirring. A sufficient quantity of water at 60° C. is thenadded with vigorous stirring to emulsify the ingredients and water thenadded q.s. 100 g.

Example 167 Sustained Release Composition

Ingredient Weight Range % Active ingredient 50-95 Microcrystallinecellulose (filler)  1-35 Methacrylic acid copolymer  1-35 Sodiumhydroxide 0.1-1.0 Hydroxypropyl methylcellulose 0.5-5.0 Magnesiumstearate 0.5-5.0

The sustained release formulations of this disclosure are prepared asfollows: compound and pH-dependent binder and any optional excipientsare intimately mixed (dry-blended). The dry-blended mixture is thengranulated in the presence of an aqueous solution of a strong base whichis sprayed into the blended powder. The granulate is dried, screened,mixed with optional lubricants (such as talc or magnesium stearate) andcompressed into tablets. Preferred aqueous solutions of strong bases aresolutions of alkali metal hydroxides, such as sodium or potassiumhydroxide, preferably sodium hydroxide, in water (optionally containingup to 25% of water-miscible solvents such as lower alcohols).

The resulting tablets may be coated with an optional film-forming agent,for identification, taste-masking purposes and to improve ease ofswallowing. The film forming agent will typically be present in anamount ranging from between 2% and 4% of the tablet weight. Suitablefilm-forming agents are well known to the art and include hydroxypropylmethylcellulose, cationic methacrylate copolymers (dimethylaminoethylmethacrylate/methyl-butyl methacrylate copolymers—Eudragit® E—Röhm.Pharma) and the like. These film-forming agents may optionally containcolorants, plasticizers and other supplemental ingredients.

The compressed tablets preferably have a hardness sufficient towithstand 8 Kp compression. The tablet size will depend primarily uponthe amount of compound in the tablet. The tablets will include fromabout 5 mg to about 1 g of compound. In certain embodiments, the tabletswill include about 5 mg, about 10 mg, about 25 mg, about 50 mg, about100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, or about750 mg of compound.

In order to influence the dissolution rate, the time during which thecompound containing powder is wet mixed is controlled. Preferably thetotal powder mix time, i.e. the time during which the powder is exposedto sodium hydroxide solution, will range from 1 to 10 minutes andpreferably from 2 to 5 minutes. Following granulation, the particles areremoved from the granulator and placed in a fluid bed dryer for dryingat about 60° C.

Example 168

Activity testing is conducted in the Examples below using methodsdescribed herein and those well known in the art.

Cardiac Sodium Current Screening Assays:

The cardiac late sodium current (Late I_(Na)) and peak sodium current(Peak I_(Na)) assays are performed on an automated electrophysiologyplatform, QPatch 16X or QPatch HT (Sophion Bioscience, Copenhagen,Denmark) using the whole cell patch clamp technique to measure currentsthrough the cell membrane. The assay uses an HEK293 (human embryonickidney) cell line heterologously expressing the wild-type human cardiacsodium channel, hNa_(v)1.5, purchased from Millipore (Billerica, Mass.).No beta subunits were coexpressed with the Na channel alpha subunit.Cells are maintained with standard tissue culture procedures and stablechannel expression is maintained with 400 μg/mL Geneticin in the culturemedium. Experiments are carried out at 23-25° C.

For both the Late I_(Na) and Peak I_(Na) assays, series resistancecompensation is set to 100% and series resistance and whole-cellcompensation are performed automatically. Currents are digitized at 25kHz and low-pass filtered at 5 kHz and stored in the Sophion BioscienceOracle database (Sophion Bioscience, Copenhagen, Denmark). Analysis isperformed using QPatch Assay software and data are compiled in Excel2010 (Microsoft, Seattle, Wash., U.S.A.).

Compound stocks are routinely made by the Gilead Sample Bank in vials to10 mM in dimethyl sulfoxide (DMSO). In some cases, when compounds arenot soluble in DMSO, they are made in 100% ethanol. Stocks are sonicatedas necessary. The extracellular solution for screening Late I_(Na) iscomposed of: 140 mM NaCl, 4 mM KCl, 1.8 mM CaCl₂, 1 mM MgCl₂, 10 mMHEPES and 10 mM Dextrose with pH adjusted to 7.35 using NaOH. Theintracellular solution contains: 105 mM CsF, 20 mM CsCl, 10 NaF, 2 mMEGTA, 10 mM HEPES and 10 mM Dextrose with pH adjusted to 7.35 with CsOH.Compounds are diluted in extracellular solution using a MicroLab Nimbus(Hamilton Robotics, Reno, Nev.) to between 0.3 and 3 μM in glass vialsand transferred to glass well plates before robotic addition to thecells. The 0 mM Na extracellular solution (0Na-ECF) used at the end ofeach experiment for the Late I_(Na) and Peak I_(Na) assays to measurebaseline current contains: 140 Choline-Cl; 4 mM KCl, 1.8 mM CaCl₂; 1 mMMgCl₂; 10 mM HEPES and 10 mM Dextrose with pH was adjusted to 7.35 withCsOH.

Late I_(Na) Screening Assay:

For the Late I_(Na) assay, sodium channels are activated every 10seconds (0.1 Hz) by depolarizing the cell membrane to −20 mV for 250milliseconds (ms) from a holding potential of −120 mV.

Compounds were tested to determine their activity in blocking the latesodium current. Late I_(Na) was generated by adding 10 μM Tefluthrin(pyrethroid) to the extracellular solution. For the purposes of thescreening, Late I_(Na) is defined as the mean current between 240 ms and265 ms during the voltage step to −20 mV. After establishing the wholecell recording configuration, Late I_(Na) activator is added to eachwell 4 times over a 15 minute period so that the late component of theNa current reaches a stable value. Compounds were then added (typicallyat 0.3 or 1 μM), in the presence of the Late I_(Na) activator, with 3additions over the course of 5 minutes. Measurements were made at theend of exposure to the third compound addition and values werenormalized to the current level when all Na⁺ was removed from theextracellular solution after two additions of 0Na-ECF.

Results are reported as percent block of late I_(Na) and results wereanalyzed by incorporating rundown correction for the Late I_(Na).

Peak I_(Na) Screening Assay:

Compounds were evaluated for their effect Na_(v)1.5 Peak I_(Na). It iscontemplated that the compounds of Formula I avoid significant block ofpeak I_(Na). Since the peak I_(Na) in the cells used herein can be verylarge, introducing artifacts in the recording, the concentration of Na⁺in the bath can be reduced to 40 mM by isosmotic replacement of Na⁺ withCholine (see below).

Tonic Block (TB) of Peak I_(Na) was measured using a voltage step to −20mV from a holding potential of −100 mV at a low stimulation frequency of0.1 Hz. Use-Dependent Block (UDB) of Peak I_(Na) was measured duringpulse number 50 of a pulse train (−20 mV, 20 ms, 50 pulses, 3 Hz) from aholding potential of −100 mV.

Block of cardiac Peak I_(Na) by compounds of this disclosure istypically increased with an increase in the frequency of stimulationfrom 0.1 to 3 Hz (frequencies encountered either in the normal heart orduring tachycardia).

The extracellular solution for screening Peak I_(Na) is composed of: 40mM NaCl, 100 mM Choline-Cl, 4 mM KCl, 1.8 mM CaCl₂, 1 mM MgCl₂ 10 mMHEPES and 10 mM Dextrose with pH adjusted to 7.35 using NaOH. Theintracellular solution used for the Peak I_(Na) assay is the same asoutlined for the Late I_(Na) assay (see above).

After establishing the whole cell recording configuration, channels werestimulated to open with low frequency (0.1 Hz) so that the recording canbe monitored and the extent to which the recording has stabilized can beassessed.

The test compound is then applied at 1 or 3 μM and was added 2 times at60 second intervals. After the second compound addition, a 200 secondwait period was imposed to allow for equilibration. Voltage protocolsfor TB and UDB are were performed in the absence and presence ofcompound and TB and UDB are calculated with respect to the compound freecondition. Both TB and UDB were analyzed by incorporating rundowncorrection for the peak I_(Na).

Compounds were tested using the above described assay methods. The dataprovided in Table 1 (in percent inhibition) was obtained by testing thelisted compounds at 1 μM and 0.3 μM concentration in the Late I_(Na) andPeak I_(Na) assays (and other concentrations as needed).

TABLE 1 Late I_(Na) Assay Results Nav1.1 Nav1.2 UDB UDB Example LateI_(Na) Late I_(Na) Peak TB Peak UDB 25 Hz 25 Hz No. 1 uM 0.3 uM 3 uM 3Hz 3 uM 10 uM 10 uM 1 66.2 55.0 5.5 10.2 2 54.6 66.1 27.9 3 52.6 23.211.8 <5 <5 4 62.9 29.7 38.0 17.9 14.2 13.9 5 54.5 38.2 18.0 <5 <5 <5 651.1 29.8 12.6 <5 <5 7 47.5 16.3 <5 <5 <5 8 52.6 13.1 <5 <5 <5 9 58.936.4 41.3 10.3 <5 <5 10 41.0 16.4 5.7 <5 <5 11 30.0 13 35.1 10.7 <5 30.85.6 14 46.7 23.8 6.4 34.5 9.6 15 32.2 14.3 <5 <5 <5 16 54.2 35.8 <5 27.318.0 17 45.9 28.9 <5 5.9 <5 18 38.2 27.7 5.2 <5 <5 19 27.5 20 28.8 2148.8 13.0 <5 <5 <5 22 55.9 17.7 10.2 <5 28.1 40.0 23 45.3 <5 <5 <5 9.924 36.0 10.0 <5 <5 <5 25 41.3 12.0 <5 <5 <5 26 49.6 27.8 <5 58.6 <5 2735.1 20.8 <5 <5 <5 28 54.4 26.7 21.6 <5 <5 <5 29 46.4 8.1 <5 <5 <5 3042.5 15.2 <5 <5 <5 31 43.9 18.5 <5 <5 <5 32 28.8 33 35.5 20.9 5.1 <5 5.534 21.0 35 33.6 17.4 <5 <5 <5 42 57.3 17.5 27.6 <5 <5 <5 43 27.1 44 48.229.9 10.4 21.1 25.4 45 43.6 16.8 15.1 63.8 42.8 46 36.8 23.7 13.9 78.447 60.2 20.0 21.7 8.5 55.5 31.5 48 51.2 9.1 5.7 52.8 54.2 49 39.6 16.9<5 56.4 49.9 50 32.5 <5 <5 49.2 27.3 51 38.8 12.3 7.7 30.0 15.7 52 24.353 57.0 31.1 43.4 <5 <5 <5 54 29.2 55 59.9 45.4 15.1 5.13 79.8 56 57.816.1 30.4 31.4 83.6 57 57.3 17.0 22.1 37.11 82.5 58 55.0 36.7 22.2 <543.5 14.5 59 60.4 43.7 19.0 <5 46.9 37.4 60 57.2 16.8 30.6 <5 27.0 <5 6138.2 11.8 6.6 28.7 31.0 62 28.4 63 44.1 39.0 13.3 77.6 68.0 64 30.7 10.1<5 33.2 34.7 65 27.0 66 21.9 67 77.4 54.4 48.7 <5 5.26 <5 68 62.2 35.810.5 <5 <5 <5 69 29.6 70 25.5 71 81.5 41.7 61.1 44.4 93.8 89.6 72 57.414.0 17.7 10.8 78.1 75.4 73 66.2 20.4 41.9 <5 10.1 <5 74 60.9 15.7 23.5<5 <5 <5 75 59.5 29.3 36.9 <5 34.2 27.1 76 55.2 49.9 <5 27.2 27.9 7749.2 34.6 8.3 49.2 31.8 78 47.1 38.7 19.5 39.9 32.8 79 46.1 26.0 <5 36.834.0 80 35.6 17.3 13.7 19.8 17.5 81 33.7 23.5 <5 <5 21.8 82 28.1 83 23.784 23.6 85 22.5 86 21.9 87 62.7 18.4 54.7 39.0 90.8 87.0 88 47.7 20.819.5 66.7 89 33.2 5.7 <5 16.1 52.0 90 20.9 91 53.0 33.0 <5 31.1 46.9 9236.3 9.6 <5 <5 <5 93 45.1 14.9 <5 <5 <5 94 58.7 35.1 17.1 <5 <5 <5 9551.7 6.4 <5 <5 <5 96 59.2 21.1 29.4 <5 29.4 5.7 97 39.0 26.5 <5 46.334.3 98 38.7 28.7 <5 15.9 <5 99 72.3 42.3 55.6 <5 30.0 50.5 100 61.931.7 23.5 <5 9.9 11.0 101 54.6 13.5 <5 <5 30.5 102 43.1 27.8 7.7 <5 20.6103 38.9 18.8 <5 8.5 <5 104 38.6 23.6 19.8 53.1 57.0 105 53.7 9.4 27.875.7 70.9 106 28.3 108 83.5 30.1 62.6 69.3 89.2 109 65.7 25.3 14.5 <557.0 39.3 110 62.7 25.7 14.5 11.5 77.7 67.3 111 35.1 <5 7.3 50.4 47.3113 79.9 43.9 54.3 37.3 88.4 91.2 114 61.2 22.5 43.4 33.3 87.1 87.0 11556.7 23.5 19.8 18.3 76.4 70.8 116 48.3 28.9 15.0 70.4 62.3 117 78.1 39.479.3 60.8 80.9 88.4 118 66.1 22.5 88.8 56.1 89.4 90.4 119 51.2 36.1 6.456.3 52.3 120 58.2 35.8 35.2 6.6 68.9 74.4 121 77.7 39.0 79. 23.4 43.657.8 122 41.3 10.7 <5 <5 29.7 123 36.3 27.3 <5 <5 <5 124 53.7 49.9 <535.0 44.9 125 41.8 <5 126 50.0 17.3 <5 <5 <5 127 37.4 23.7 25.1 82.876.5 128 42 17.3 <5 <5 <5 129 67.5 34.3 33.5 130 38.3 9.2 <5 <5 <5 13124.8 132 40.5 20.6 5.1 <5 <5 133 45.8 38.8 5.2 22.1 29.2 134 21.1 13548.8 19.7 29.3 18.0 87.2 76.5 136 44.8 10.5 <5 <5 <5 137 47.2 43.9 17.482.6 86.0 138 29.8 139 41.2 15.6 <5 8.8 26.1 140 37.6 8.5 <5 <5 <5 14138.6 17.8 <5 31.5 19.9 142 44.0 15.6 13.9 59.0 65.0 143 60.3 35.9 39.811.2 66.6 57.1 144 55.7 25.9 46.9 <5 73.2 75.8 145 84.9 61.7 93.0 <581.4 75.8 146 48.4 28.8 25.5 87.3 75.8 147 45.4 26.0 3.0 32.0 20.4 14837.3 17.9 <5 <5 <5 149 87.6 50.9 86.4 <5 50.0 44.4 150 68.2 49.4 58.59.3 62.8 51.0 151 70.1 50.7 43.3 <5 20.0 18.6 152 53.4 19.8 30.6 <5 11.413.8 153 67.6 51.3 57.6 73.1 53.7 154 39.2 7.68 <5 19.8 27.0 155 69.247.0 24.8 8.4 63.5 58.6 156 62.8 37.9 10.4 <5 26.5 10.6 157 36.9 15.6 <5<5 <5 158 37.3 17.9 <5 <5 <5

The assay results shown in Table 1 establish that compounds testedshowed activity as modulators of late sodium current, for example byinhibiting (or reducing) the late sodium current.

In some embodiments the effects of a compound of Formula I are specificfor the late sodium current and show little or no activity with respectto one or more other ion channels. Thus, in some embodiments, a compoundhaving an activity of reducing late sodium current will also exhibitlittle or no activity with regard to the peak sodium current.

Example 169 Use-Dependent Inhibition of the CNS Na_(v)1.1 Sodium Channel

Expression of Human Na_(v)1.1 cDNA

HEK-293 cells stably expressing wild-type (WT) hNa_(v)1.1 (SCN1A, NCBI #AB09354) were obtained from Millipore (Cat. # CYL3009) were used torecord I_(Na). Cells are maintained with standard tissue cultureprocedures and stable channel expression is maintained with 400 ug/mLG418 in the culture medium. Unless otherwise noted, all reagents arepurchased from Sigma-Aldrich (St Louis, Mo., U.S.A.).

Electrophysiology

Assays measuring Use-Dependent Block (UDB) of Na_(v)1.2 are performed onan automated electrophysiology platform, QPatch 16X or QPatch HT(Sophion Bioscience, Copenhagen, Denmark), using the whole cell patchclamp technique to measure currents through the cell membrane. Seriesresistance compensation is set to 100% and series resistance andwhole-cell compensation are performed automatically. Currents stored inthe Sophion Bioscience Oracle database (Sophion Bioscience, Copenhagen,Denmark). Analysis is performed using QPatch Assay software and data arecompiled in Excel 2010 (Microsoft, Seattle, Wash., U.S.A.).

The internal (pipette) solution consists of (in mM) 105 CsF, 10 NaF, 20CsCl, 2 EGTA, 10 HEPES, 10 Dextrose with a pH of 7.35 and osmolarity of300 mOsmol/kg. The external (bath) solution contains in (mM): 145 NaCl,4 KCl, 1.8 CaCl₂, 1 MgCl₂, 10 dextrose, 10 HEPES, with a pH of 7.35 andosmolarity of 310 mOsmol/kg. Experiments are carried out at 23-25° C.

Compound stocks are routinely made by the Gilead Sample Bank in vials to10 mM in dimethyl sulfoxide (DMSO). In some cases, when compounds arenot soluble in DMSO, they are made in 100% ethanol. Stocks are sonicatedas necessary. Compounds are diluted in extracellular solution using aMicroLab Nimbus (Hamilton Robotics, Reno, Nev.) to between 0.3 and 3 μMin glass vials and transferred to glass well plates before roboticaddition to the cells.

Cells are allowed to stabilize for 10 min after establishment of thewhole-cell configuration before current is measured. The test compoundis applied 2 times at 60 second intervals. After the second compoundaddition, a 200 second wait period was imposed to allow forequilibration. Leak currents are subtracted by using an online P/4procedure and all currents are low-pass Bessel filtered at 5 kHz anddigitized at 525 kHz.

Use-dependent block of Na_(v)1.2 peak current is measured during pulsenumber 20 of a voltage pulse train (0 mV, 20 ms, 20 pulses, 25 Hz) froma holding potential of −120 mV. Currents are normalized to the peakcurrent recorded in response to the first pulse in each frequency train.The voltage protocol for UDB was performed in the absence and presenceof compound and percentage inhibition was calculated with respect to thecompound free condition. Results are presented as mean percentageinhibition and data analysis is performed using QPatch Assay Software4.0, and Excel 2002 (Microsoft, Seattle, Wash., U.S.A.).

Example 170 Use-Dependent Inhibition of the CNS Na_(v)1.2 Sodium Channel

Expression of Human Na_(v)1.2 cDNA

HEK-293 cells stably expressing wild-type (WT) hNaV1.2 (SCN2A NCBI #NM_021007.2, SCN1B NCBI # NM_001037.4, SCN2B NCBI # NM_004588.2) wereused to record I_(Na). Cells are maintained with standard tissue cultureprocedures and stable channel expression is maintained with 800 ug/mLG418 and 3 ug/mL Puromycin in the culture medium. Unless otherwisenoted, all reagents are purchased from Sigma-Aldrich (St Louis, Mo.,U.S.A.).

Electrophysiology

Assays measuring Use-Dependent Block (UDB) of Na_(v)1.2 are performed onan automated electrophysiology platform, QPatch 16X or QPatch HT(Sophion Bioscience, Copenhagen, Denmark), using the whole cell patchclamp technique to measure currents through the cell membrane. Seriesresistance compensation is set to 100% and series resistance andwhole-cell compensation are performed automatically. Currents stored inthe Sophion Bioscience Oracle database (Sophion Bioscience, Copenhagen,Denmark). Analysis is performed using QPatch Assay software and data arecompiled in Excel 2010 (Microsoft, Seattle, Wash., U.S.A.).

The internal (pipette) solution consists of (in mM) 105 CsF, 10 NaF, 20CsCl, 2 EGTA, 10 HEPES, 10 Dextrose with a pH of 7.35 and osmolarity of300 mOsmol/kg. The external (bath) solution contains in (mM): 145 NaCl,4 KCl, 1.8 CaCl₂, 1 MgCl₂, 10 dextrose, 10 HEPES, with a pH of 7.35 andosmolarity of 310 mOsmol/kg. Experiments are carried out at 23-25° C.

Compound stocks are routinely made by the Gilead Sample Bank in vials to10 mM in dimethyl sulfoxide (DMSO). In some cases, when compounds arenot soluble in DMSO, they are made in 100% ethanol. Stocks are sonicatedas necessary. Compounds are diluted in extracellular solution using aMicroLab Nimbus (Hamilton Robotics, Reno, Nev.) to between 0.3 and 3 μMin glass vials and transferred to glass well plates before roboticaddition to the cells.

Cells are allowed to stabilize for 10 min after establishment of thewhole-cell configuration before current is measured. The test compoundis applied 2 times at 60 second intervals. After the second compoundaddition, a 200 second wait period was imposed to allow forequilibration. Leak currents are subtracted by using an online P/4procedure and all currents are low-pass Bessel filtered at 5 kHz anddigitized at 525 kHz.

Results are presented as mean percentage inhibition.

Use-dependent block of Na_(v)1.2 peak current is measured during pulsenumber 20 of a voltage pulse train (0 mV, 20 ms, 20 pulses, 25 Hz) froma holding potential of −120 mV.

Currents are normalized to the peak current recorded in response to thefirst pulse in each frequency train. The voltage protocol for UDB wasperformed in the absence and presence of compound and percentageinhibition was calculated with respect to the compound free condition.

Data analysis is performed using QPatch Assay Software 4.0, and Excel2002 (Microsoft, Seattle, Wash., U.S.A.).

Using the above methods it may be demonstrated that the compounds of thedisclosure are selective for inhibiting cardiac Late I_(Na) currentwithout inhibiting peak currents of brain isoforms Na_(v)1.1 andNa_(v)1.2. The compounds of the disclosure may inhibit the very highfrequency firing of Na_(v)1.1 and Na_(v)1.2 or demonstrate voltagedependent block of mutant Na_(v)1.1 and Na_(v)1.2 observed with epilepsypatients. Data for sample compounds is shown above in Table 1.

Example 171 Voltage-Dependent Inhibition of the Na_(v)1.3 Sodium Channel

Expression of Human Na_(v)1.3 cDNA

HEK-293 cells stably expressing wild-type (WT) hNa_(v)1.3 (SCN3A NCBI #NP_001075, SCN1B NCBI # NM_001037.4, SCN2B NCBI # NM_004588.2) were usedto record I_(Na). Cells are maintained with standard tissue cultureprocedures and stable channel expression is maintained with 800 ug/mLG418 and 3 ug/mL Puromycin in the culture medium. Unless otherwisenoted, all reagents are purchased from Sigma-Aldrich (St Louis, Mo.,U.S.A.).

Electrophysiology

Assays measuring Voltage-Dependent Block (VDB) of Na_(v)1.3 areperformed on an automated electrophysiology platform, QPatch 16X orQPatch HT (Sophion Bioscience, Copenhagen, Denmark), using the wholecell patch clamp technique to measure currents through the cellmembrane. Series resistance compensation is set to 100% and seriesresistance and whole-cell compensation are performed automatically.Currents stored in the Sophion Bioscience Oracle database (SophionBioscience, Copenhagen, Denmark). Analysis is performed using QPatchAssay software and data are compiled in Excel 2010 (Microsoft, Seattle,Wash., U.S.A.).

The internal (pipette) solution consists of (in mM) 105 CsF, 10 NaF, 20CsCl, 2 EGTA, 10 HEPES, 10 Dextrose with a pH of 7.35 and osmolarity of300 mOsmol/kg. The external (bath) solution contains in (mM): 80 NaCl,60 Choline-Cl, 4 KCl, 1.8 CaCl₂, 1 MgCl₂, 10 dextrose, 10 HEPES, with apH of 7.35 and osmolarity of 310 mOsmol/kg. Experiments are carried outat 23-25° C.

Compound stocks are routinely made by the Gilead Sample Bank in vials to10 mM in dimethyl sulfoxide (DMSO). In some cases, when compounds arenot soluble in DMSO, they are made in 100% ethanol. Stocks are sonicatedas necessary. Compounds are diluted in extracellular solution using aMicroLab Nimbus (Hamilton Robotics, Reno, Nev.) to 1 μM in glass vialsand transferred to glass well plates before robotic addition to thecells.

Cells are allowed to stabilize for 10 min after establishment of thewhole-cell configuration before current is measured. The test compoundis applied 3 times at 120 second intervals to allow for equilibration.Currents were leak subtracted using a P/4 procedure, low-pass Besselfiltered at 5 kHz and digitized at 25 kHz. Results are presented as meanpercentage inhibition.

Voltage-dependent block of Na_(v)1.3 peak current was measured during avoltage step to 0 mV (20 ms) following a voltage step pre-conditioningsteps (−55 mV for 10 sec followed by −120 mV for 10 ms). The holdingpotential was −120 mV and this voltage protocol induces half maximalinactivation of Na_(v)1.3. The voltage protocol for VDB was performedevery 45 seconds in the absence and presence of compound and percentageinhibition was calculated with respect to the compound free condition.

Voltage-Dependent Inhibition of the Na_(v)1.7 Sodium Channel

Expression of Human Na_(v)1.7 cDNA

HEK-293 cells stably expressing wild-type (WT) hNa_(v)1.7 were obtainedfrom Scottish Biomedical (Glasgow, Scotland, United Kingdom). Cells aremaintained with standard tissue culture procedures and stable channelexpression is maintained with 500 ug/mL G418 in the culture medium.Unless otherwise noted, all reagents are purchased from Sigma-Aldrich(St Louis, Mo., U.S.A.).

Electrophysiology

Assays measuring Voltage-Dependent Block (VDB) of Na_(v)1.7 areperformed on an automated electrophysiology platform, QPatch 16X orQPatch HT (Sophion Bioscience, Copenhagen, Denmark), using the wholecell patch clamp technique to measure currents through the cellmembrane. Series resistance compensation is set to 100% and seriesresistance and whole-cell compensation are performed automatically.Currents stored in the Sophion Bioscience Oracle database (SophionBioscience, Copenhagen, Denmark). Analysis is performed using QPatchAssay software and data are compiled in Excel 2010 (Microsoft, Seattle,Wash., U.S.A.).

The internal (pipette) solution consists of (in mM) 105 CsF, 10 NaF, 20CsCl, 2 EGTA, 10 HEPES, 10 Dextrose with a pH of 7.35 and osmolarity of300 mOsmol/kg. The external (bath) solution contains in (mM): 140 NaCl,4 KCl, 1.8 CaCl₂, 1 MgCl₂, 10 dextrose, 10 HEPES, with a pH of 7.35 andosmolarity of 310 mOsmol/kg. Experiments are carried out at 23-25° C.

Compound stocks are routinely made by the Gilead Sample Bank in vials to10 mM in dimethyl sulfoxide (DMSO). In some cases, when compounds arenot soluble in DMSO, they are made in 100% ethanol. Stocks are sonicatedas necessary. Compounds are diluted in extracellular solution using aMicroLab Nimbus (Hamilton Robotics, Reno, Nev.) to 1 μM in glass vialsand transferred to glass well plates before robotic addition to thecells.

Cells are allowed to stabilize for 10 min after establishment of thewhole-cell configuration before current is measured. The test compoundis applied 3 times at 120 second intervals to allow for equilibration.Currents were leak subtracted using a P/4 procedure, low-pass Besselfiltered at 5 kHz and digitized at 25 kHz. Results are presented as meanpercentage inhibition.

Voltage-dependent block of Na_(v)1.7 peak current was measured during avoltage step to 0 mV (20 ms) following a voltage step pre-conditioningsteps (−60 mV for 10 sec followed by −120 mV for 10 ms). The holdingpotential was −120 mV and this voltage protocol induces half maximalinactivation of Na_(v)1.7. The voltage protocol for VDB was performedevery 45 seconds in the absence and presence of compound and percentageinhibition was calculated with respect to the compound free condition.

Using the above methods it may be demonstrated that select compounds ofthe disclosure also exhibit voltage-dependent block of Na_(v)1.3 andNa_(v)1.7. This activity is thought to correlate with potentialantidiabetic effects of the compounds. The VDB protocols produce halfmaximal inactivation of the peak I_(Na) and also mimic the restingmembrane potential of pancreatic islet cells (beta, alpha and deltacells). Data for exemplary compounds is shown below in Table 2.

TABLE 2 Na_(v)1.3 and Na_(v)1.7 Assay results Nav 1.3-VDB Nav 1.7-VDBExample 1 uM 1 uM 4 12.2 28.6 5 13.9 6 <5 15.6 7 <5 8 6.4 10 8.5 10.0 2111.2 22 17.3 24 <5 25 12.3 29 39.5 34.2 30 21.5 51 26.6 59 14.5 61 8.668 27.1 99 41.4 59.3 158 <5

Example 172 Ischemia-Induced ST Segment Elevation in AnesthetizedRabbits

This study was undertaken to determine the anti-ischemic effects ofcompounds of the present disclosure in an in vivo rabbit model.

Methods:

Female New Zealand rabbits (3.0-4.0 kg) were purchased from WesternOregon Rabbitry. Animals were housed on a 12-h light and dark cycle andreceived standard laboratory chow and water. All experiments wereperformed in accordance with the Guide for the Care and Use ofLaboratory Animals published by The National Research Council and withthe experimental protocol approved by the Institutional Animal CareCommittee of Gilead Sciences, Inc.

Rabbits were anesthetized with ketamine (35 mg/kg) and xylazine (5mg/kg) intramuscular injection (im). A tracheotomy was performed and thetrachea was intubated with an endrotracheal tube. The animal wasventilated with room air supplemented with oxygen using a pressurecontrol animal ventilator (Kent Scientific Corp., Torrington, Conn.) ata respiratory rate of 40 strokes/min and peak inspiration pressure of 10mmH₂O, which was adjusted to keep blood gases and pH within thephysiological range (iSTAT clinic analyzer, Heska Corp.; Waukesha,Wis.). The left femoral artery was cannulated for the measurement ofblood pressure (BP). Blood samples were also withdrawn from femoralartery. The right external jugular vein was cannulated for drug/vehicleadministration. Needle electrodes were inserted subcutaneously into thelimbs for recording of the surface electrocardiogram (ECG).

The heart was exposed via an incision in the 4^(th) intercostal space(4^(th) and/or 5^(th) ribs were cut for a clear surgical vision). Thechest was opened and a pericardial cradle was formed using 4 retractors.A coronary artery occluder, comprised of a snare made of 5 cm PE-10tubing with a 6-0 Prolene polypropylene suture in it, was placed looselyaround the left anterior descending artery (LAD) at its origin. Twounipolar electrodes, made with teflon coated silver wire attached to asmall patch of filter paper, were attached on the surface of theischemic and normal regions of the left ventricle to record epicardialelectrocardiogram.

Reference electrodes were placed in the open incision of the neck. Thebody temperature of the animal was monitored via a rectal thermometerand maintained at 37-40° C. by adjusting the surface temperature of thesurgical table. Regional ischemia (15 min) was induced by ligating theLAD followed by 15 min of reperfusion caused by releasing the ligation.The heart was excised at the end of the experiment and the LAD wasre-ligated. The ischemic area was visualized by perfusing the heart with1% Evans blue in saline and calculated as a percentage of totalventricular weight. Rabbits with ischemic area less than 10% or largerthan 25% were excluded from the analysis. Animals were randomly assignedto vehicle and test compound groups. Test compounds were dissolved in15% NMP, 10% Solutol and 75% de-ionized water (dH₂O). Test compoundswere given as an iv infusion at a rate targeted to reach plasmaconcentrations of 1 μM. After 30 min of compound administration theheart was subjected to 15 min of ischemia followed by 15 min ofreperfusion.

Results:

The data in Table 3 suggests certain compounds of the disclosure mayprevent ischemia-induced myocardial electrical dysfunction.

TABLE 3 Ischemia-induced ST segment elevation results Rabbit ST PlasmaExample No. Segment* concentration 1 32   1 uM 5 0 1.4 uM 6 0 0.8 uM 5814 1.3 uM 59 23 1.3 uM 96 46   1 uM 21 66 0.4 uM *Percent reduction

What is claimed is: 1-32. (canceled)
 33. A method of treating a diseasestate in a human that is alleviable by treatment with an agent capableof reducing late sodium current, comprising administering to a human inneed thereof a therapeutically effective dose of a compound selectedfrom the group consisting of:

or a pharmaceutically acceptable salt, stereoisomer or mixture ofstereoisomer thereof.
 34. A method of treating a disease state in ahuman that is alleviable by treatment with an agent capable of reducinglate sodium current, comprising administering to a human in need thereofa therapeutically effective dose of a compound selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.
 35. The method of claim33, wherein the disease state is a cardiovascular disease selected fromone or more of atrial arrhythmias, ventricular arrhythmias, heartfailure (including congestive heart failure, diastolic heart failure,systolic heart failure, acute heart failure), Prinzmetal's (variant)angina, stable angina, unstable angina, exercise induced angina,congestive heart disease; ischemia, recurrent ischemia, reperfusioninjury, myocardial infarction, acute coronary syndrome, peripheralarterial disease, pulmonary hypertension, long QT syndrome, hypertrophiccardiomyopathy and intermittent claudication.
 36. The method of claim34, wherein the disease state is a cardiovascular disease selected fromone or more of atrial arrhythmias, ventricular arrhythmias, heartfailure (including congestive heart failure, diastolic heart failure,systolic heart failure; acute heart failure), Prinzmetal's (variant)angina, stable angina, unstable angina, exercise induced angina,congestive heart disease, ischemia, recurrent ischemia, reperfusioninjury, myocardial infarction, acute coronary syndrome, peripheralarterial disease, pulmonary hypertension, long OT syndrome, hypertrophiccardiomyopathy and intermittent claudication.
 37. The method of 33,wherein the disease state is diabetes or diabetic peripheral neuropathy.38. The method of 33, wherein the disease state results in one or moreof neuropathic pain, epilepsy, migraine, seizures or paralysis.
 39. Themethod of 34, wherein the disease state is diabetes or diabeticperipheral neuropathy.
 40. The method of 34, wherein the disease stateresults in one or more of neuropathic pain, epilepsy, migraine, seizuresor paralysis.